Transferring from clopidogrel loading dose to prasugrel loading dose in acute coronary syndrome patients. High on-treatment platelet reactivity analysis of the TRIPLET trial.

High on-treatment platelet reactivity (HPR) has been identified as an independent risk factor for ischaemic events. The randomised, double-blind, TRIPLET trial included a pre-defined comparison of HPR in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) following a placebo/600-mg clopidogrel loading dose (LD) immediately before a subsequent prasugrel 60-mg or 30-mg LD. Platelet reactivity was assessed using the VerifyNow® P2Y12 assay (P2Y12 Reaction Units, PRU) within 24 hours (h) following the placebo/clopidogrel LD (immediately prior to prasugrel LD), and at 2, 6, 24, 72 h following prasugrel LDs. The impact of CYP2C19 predicted metaboliser phenotype (extensive metabolisers [EM] and reduced metabolisers [RM]) on HPR status was also assessed. HPR (PRU ≥240) following the clopidogrel LD (prior to the prasugrel LD) was 58.5% in the combined clopidogrel LD groups. No significant difference was noted when stratified by time between the clopidogrel and prasugrel LDs (≤6 hs vs>6 h). At 6 h following the 2nd loading dose in the combined prasugrel LD groups, HPR was 7.1%, with 0% HPR by 72 h. There was no significant effect of CYP2C19 genotype on pharmacodynamic (PD) response following either prasugrel LD treatments at any time point, regardless of whether it was preceded by a clopidogrel 600-mg LD. In conclusion, in this study, patients with ACS intended for PCI showed a high prevalence of HPR after clopidogrel 600-mg LD regardless of metaboliser status. When prasugrel LD was added, HPR decreased substantially by 6 h, and was not seen by 72 h.

How valid are utilization review tools in assessing appropriate use of acute care beds?

BACKGROUND: Despite their widespread acceptance, utilization review tools, which were designed to assess the appropriateness of care in acute care hospitals, have not been well validated in Canada. The aim of this study was to assess the validity of 3 such tools--ISD (Intensity of service, Severity of illness, Discharge screens), AEP (Appropriateness Evaluation Protocol) and MCAP (Managed Care Appropriateness Protocol)--as determined by their agreement with the clinical judgement of a panel of experts. METHODS: The cases of 75 patients admitted to an acute cardiology service were reviewed retrospectively. The criteria of each utilization review tool were applied by trained reviewers to each day the patients spent in hospital. An abstract of each case prepared in a day-by-day format was evaluated independently by 3 cardiologists, using clinical judgement to decide the appropriateness of each day spent in hospital. RESULTS: The panel considered 92% of the admissions and 67% of the subsequent hospital days to be appropriate. The ISD underestimated the appropriateness rates of admission and subsequent days; the AEP and MCAP overestimated the appropriateness rate of subsequent days in hospital. The kappa statistic of overall agreement between tool and panel was 0.45 for ISD, 0.24 for MCAP and 0.25 for AEP, indicating poor to fair validity of the tools. INTERPRETATION: Published validation studies had average kappa values of 0.32-0.44 (i.e., poor to fair) for admission days and for subsequent days in hospital for the 3 tools. The tools have only a low level of validity when compared with a panel of experts, which raises serious doubts about their usefulness for utilization review.

Combination therapy with tirofiban and enoxaparin in acute coronary syndromes.

BACKGROUND: Tirofiban, an intravenous glycoprotein IIb/IIIa antagonist, and enoxaparin, a low molecular weight heparin, have each been shown to be effective at reducing cardiac ischemic events compared to unfractionated heparin alone in separate trials of patients with unstable angina and non-Q-wave myocardial infarction. The combination of these agents may offer further therapeutic benefit. MATERIALS AND METHODS: Fifty-five patients with non-Q-wave myocardial infarction were randomized to receive double-blind treatment with tirofiban (0.1 microgram/kg/min i.v.) for 48-108 h coadministered with either enoxaparin (1 mg/kg sc q 12 h) (n=26) or unfractionated heparin (i.v. adjusted to activated partial-thromboplastin time) (n=27) to evaluate pharmacokinetics, pharmacodynamics, and safety. The primary objective of the study was to investigate the effect of unfractionated heparin versus enoxaparin on the plasma clearance of tirofiban. RESULTS: Coadministration of tirofiban and enoxaparin was generally well tolerated. Plasma clearance of tirofiban was 176.7+/-59.8 and 187.5+/-81.8 ml/min, respectively, for enoxaparin and unfractionated heparin-treated patients (P=NS). The mean difference was well within the prespecified criterion for comparability. Administration of tirofiban with enoxaparin vs. unfractionated heparin resulted in lesser variability and a trend towards greater inhibition of platelet aggregation using 5 microM adenosine phosphate agonist. More patients achieved target inhibition of platelet aggregation >70% in the tirofiban and enoxaparin group (84% vs. 65%, P=0.19). Median bleeding time was 21 min for tirofiban and enoxaparin vs. > or =30 min for tirofiban and unfractionated heparin (P=NS). For a given level of inhibition of platelet aggregation, bleeding time was less prolonged with tirofiban and enoxaparin than tirofiban and unfractionated heparin (adjusted mean bleeding time 19.6 vs. 24.9 min, P=0.02). Tirofiban plasma concentration and clearance were comparable whether coadministered with enoxaparin or unfractionated heparin. There were no major or minor bleeding events in either group by the TIMI criteria. INTERPRETATION: The more consistent inhibition of platelet aggregation and lower adjusted bleeding time of tirofiban and enoxaparin vs. tirofiban and unfractionated heparin support the therapeutic potential of combining these two agents. These data from the first clinical report of coadministration of a glycoprotein IIb/IIIa receptor antagonist and a low molecular weight heparin are consistent with prior data which show differential pharmacodynamic effects of enoxaparin and unfractionated heparin on platelet aggregation.

Effect of atherosclerosis on endothelium-dependent inhibition of platelet activation in humans.

BACKGROUND: We investigated whether luminal release of nitric oxide (NO) contributes to inhibition of platelet activation and whether these effects are reduced in patients with atherosclerosis. METHODS AND RESULTS: Femoral blood flow velocity and ex vivo whole blood platelet aggregation by impedance aggregometry were measured in femoral venous blood during femoral arterial infusion of acetylcholine (ACh; 30 microg/min) in 30 patients, 19 of whom had angiographic atherosclerosis. Measurements were repeated with sodium nitroprusside (40 microg/min), L-arginine (160 micromol/min), and N(G)-monomethyl-L-arginine (L-NMMA; 16 micromol/min). There was significant inhibition of collagen-induced platelet aggregation with ACh (45+/-9.5% lower, P<0.001), and this inhibition was greater in patients without atherosclerosis (68.7+/-10.4% reduction) than in those with atherosclerosis (32.5+/-8.1%, P=0.04). The magnitude of inhibition correlated with vasodilation with ACh, indicating an association between the smooth muscle and antiplatelet effects of endothelium-dependent stimulation. Neither L-NMMA nor sodium nitroprusside altered platelet aggregation. L-Arginine inhibited platelet aggregation equally in vitro (34+/-8% reduction, P<0.01) and in vivo (37+/-13% reduction, P<0.01). CONCLUSIONS: Stimulation of NO release into the vascular lumen with ACh inhibits platelet aggregation, an effect that is attenuated in patients with atherosclerosis and endothelial dysfunction. Basal NO release does not appear to contribute to platelet passivation in vivo. L-Arginine inhibited platelet aggregation by its direct action on platelets. These findings provide a pathophysiological basis for the observed increase in thrombotic events in atherosclerosis. Use of L-arginine and other strategies to improve endothelial NO activity may impact favorably on thrombotic events in atherosclerosis.

The delay to thrombolysis: an analysis of hospital and patient characteristics. Quebec Acute Coronary Care Working Group.

OBJECTIVE: To describe the various components of the delay to thrombolytic treatment for patients with acute myocardial infarction (MI) and to identify the hospital and patient characteristics related to these delays. DESIGN: Cohort analysis from a hospital registry of patients receiving thrombolytic treatment. SETTING: Forty acute care hospitals in Quebec. SUBJECTS: All 1357 patients who received thrombolysis between January 1995 and May 1996. MAIN OUTCOME MEASURES: Time from onset of symptoms to arrival at hospital and the various components of the in-hospital delay. RESULTS: The median delay before presentation to hospital was 98 (interquartile range [IR] 56 to 180) minutes and was longer for women (p < 0.001), patients over 65 years of age (p < 0.001) and patients with diabetes mellitus (p < 0.01). The median time from arrival at hospital to thrombolysis was 59 (IR 41 to 89) minutes, the medical decision-making component taking a median of 12 (IR 4 to 27) minutes. Women (p < 0.005), older patients (p < 0.001) and patients with a past history of MI (p < 0.001) had increased in-hospital delays to thrombolysis. Delays were longer in community hospitals (p < 0.05) and low-volume centres (p < 0.01) and when a cardiologist made the decision to administer thrombolysis (p < 0.001). Multivariate analysis showed that increased age (odds ratio 1.5, 95% confidence interval 1.3 to 1.7, p < 0.001) and having the medical decision made by a cardiologist (odds ratio 1.8, 95% confidence interval 1.6 to 2.0, p < 0.001) were independently associated with an increased risk of being in the upper median of in-hospital delays. CONCLUSIONS: Despite certain improvements, there remain substantial delays between symptom onset and the administration of thrombolysis for patients with acute MI. A large part of the delay is due to the hesitation of patients (particularly women, older patients and patients with diabetes) to seek medical attention. Although the median time for medical decision-making appears reasonable, care must be taken to ensure that all patient groups receive timely evaluation and therapy. The delay associated with having the treatment decision made by a cardiologist probably represents a marker for more difficult, complex cases. Methods should be developed to permit specialty consultation, if needed, while minimizing treatment delays. Community and low-volume hospitals may require special attention.

Effect of L-arginine on human coronary endothelium-dependent and physiologic vasodilation.

OBJECTIVES: We hypothesized that L-arginine would improve abnormal coronary vasodilation in response to physiologic stress in patients with atherosclerosis and its risk factors by reversing coronary endothelial dysfunction. BACKGROUND: Studies have demonstrated that physiologic coronary vasodilation correlates with endothelial function and that L-arginine, the substrate for nitric oxide synthesis, improves the response to acetylcholine (Ach). METHODS: Changes in coronary blood flow and epicardial diameter response to Ach, adenosine and cardiac pacing were measured in 32 patients with coronary atherosclerosis or its risk factors and in 7 patients without risk factors and normal coronary angiograms. RESULTS: Intracoronary L-arginine did not alter baseline coronary vascular tone, but the epicardial and microvascular responses to Ach were enhanced (both p < 0.001). The improvement after L-arginine was greater in epicardial segments that initially constricted with Ach; similarly, L-arginine abolished microvascular constriction produced by higher doses of Ach. Thus, there was a negative correlation between the initial epicardial and vascular resistance responses to Ach and the magnitude of improvement with L-arginine (r = -0.55 and r = -0.50, respectively, p < 0.001). D-Arginine did not affect the responses to Ach, and adenosine responses were unchanged with L-arginine. Cardiac pacing-induced epicardial constriction was abolished by L-arginine, but microvascular dilation remained unaffected. CONCLUSIONS: Thus, L-arginine improved endothelium-dependent coronary epicardial and microvascular function in patients with endothelial dysfunction. Prevention of epicardial constriction during physiologic stress by L-arginine in patients with endothelial dysfunction may be of therapeutic value in the treatment of myocardial ischemia.

Platelet membrane receptor glycoprotein IIb/IIIa antagonism in unstable angina. The Canadian Lamifiban Study.

BACKGROUND: Ligand binding to the platelet membrane receptor glycoprotein (GP) IIb/IIIa, the final and obligatory step to platelet aggregation, can now be inhibited by pharmacological agents. This study was designed to evaluate the potential of lamifiban, a novel nonpeptide antagonist of GP IIb/IIIa, for the management of unstable angina. METHODS AND RESULTS: In a prospective, dose-ranging, double-blind study, 365 patients with unstable angina were randomized to an infusion of 1, 2, 4, or 5 micrograms/min of lamifiban or of placebo. Treatment was administered for 72 to 120 hours. Outcome events were measured during the infusion period and after 1 month. Concomitant aspirin was administered to all patients and heparin to 28% of patients. Lamifiban, all doses combined, reduced the risk of death, nonfatal myocardial infarction, or the need for an urgent revascularization during the infusion period from 8.1% to 3.3% (P = .04). The rates were 2.5%, 4.9%, 3.3%, and 2.4% with increasing doses. At 1 month, death or nonfatal infarction occurred in 8.1% of patients with placebo and in 2.5% of patients with the two high doses (P = .03). The highest dose of lamifiban additionally prevented the need for an urgent intervention. Lamifiban dose-dependently inhibited platelet aggregation. Bleeding times were significantly prolonged with platelet inhibition of > 80%. Major (but neither life-threatening nor intracranial) bleedings occurred in 0.8% of patients with placebo and 2.9% with lamifiban. CONCLUSIONS: The nonpeptide GP IIb/IIIa antagonist lamifiban protected patients with unstable angina from severe ischemic events during a 3- to 5-day infusion and reduced the incidence of death and infarction at 1 month, suggesting considerable promise for this new therapeutic approach.

Inhibitory effect of nitroglycerin and sodium nitroprusside on platelet activation across the coronary circulation in stable angina pectoris.

This study assessed the inhibitory effect of nitroglycerin and sodium nitroprusside on platelet aggregation in a model of platelet activation across coronary circulation. Platelet aggregation is believed to contribute to the precipitation of acute ischemic syndromes. We previously showed that rapid atrial pacing in patients with stable coronary artery disease (CAD) causes platelet hyperaggregability during blood passage in coronary circulation. Because nitroglycerin and sodium nitroprusside have been shown to inhibit platelet aggregation, we examined the effect of these drugs on this model of platelet activation. During catheterization of 19 patients with CAD (> 50% diameter narrowing of epicardial coronary arteries), we measured platelet aggregation (using whole blood platelet aggregometry) on blood samples obtained simultaneously from the coronary sinus and aorta at rest, and 2 minutes after onset of rapid atrial pacing. This procedure was repeated during an intravenous infusion of either nitroglycerin (n = 9) or sodium nitroprusside (n = 10). There was no arteriovenous difference in platelet aggregation under resting conditions. Atrial pacing caused an increase in platelet aggregation in coronary sinus blood (+64 +/- 9%; p < 0.01), but not in arterial blood (15 +/- 12% decrease; p = NS). This increase was transient and returned toward baseline 10 minutes after termination of pacing. Although resting platelet aggregation was not affected by nitroglycerin or sodium nitroprusside, activation of platelets with atrial pacing across the coronary bed was stopped by pretreatment with therapeutic doses of nitroglycerin or sodium nitroprusside. When coronary blood flow increases in patients with CAD, platelets are activated and aggregate more easily. This activation can be blunted by pretreatment with nitroglycerin or sodium nitroprusside.(ABSTRACT TRUNCATED AT 250 WORDS)

Improvement of the age-related impairment in left ventricular diastolic filling with verapamil in the normal human heart.

BACKGROUND: Left ventricular (LV) diastolic function declines with the normal aging process. Because these changes are related to impaired active LV relaxation as well as to structural alterations, we hypothesized that verapamil might improve LV filling in elderly normal subjects compared with young normal subjects. METHODS AND RESULTS: We studied 27 normal volunteers (between 20 and 71 years old), with normal exercise tests and echocardiograms, by radionuclide angiography before and after 3 to 4 days of oral verapamil therapy. Indexes of global LV function were derived from analysis of background-corrected time-activity curves. Subjects were recruited from three age groups: young (26 +/- 4 years, n = 10), middle-aged (46 +/- 5 years, n = 9), and elderly (66 +/- 3 years, n = 8). Baseline resting heart rate, blood pressure, peak systolic wall stress, and LV ejection fraction did not differ among groups. Baseline peak LV filling rate (expressed in fractional stroke volume per second) was reduced in the middle-aged group (5.8 +/- 1.2, P < .01) and the elderly group (4.3 +/- 1.0, P < .01) compared with the young group (7.8 +/- 1.2). With verapamil, resting heart rate, peak systolic wall stress, LV ejection fraction, and peak ejection rate did not change in any group. Peak filling rate increased in the middle-aged group (to 6.8 +/- 1.5 SV/s, P < .01) and the elderly group (to 5.7 +/- 1.0 SV/s, P < .01) but did not change in the young group (8.0 +/- 1.4 SV/s). Also, time to peak filling rate decreased with verapamil in the elderly group (from 185 +/- 31 to 147 +/- 15 milliseconds, P < .01). The magnitude of change in filling rate was correlated positively with age (r = .55, P < .005). CONCLUSION: Verapamil selectively enhances LV diastolic filling in middle-aged and elderly subjects, compared with young adults, without affecting systolic function. This observation supports the hypothesis that the impairment of LV filling accompanying the normal aging process is, at least in part, a reversible phenomenon.

Platelet activation in stable coronary artery disease.

To elucidate the role of physical activity in the pathogenesis of acute ischemic syndromes in patients with coronary artery disease (CAD), we hypothesized that platelet activation occurs when coronary blood flow velocity and shear stress increase across an atherosclerotic vascular bed. We measured platelet aggregation by using angiologic catheterization to obtain simultaneous samples of whole blood from the coronary sinus and the aorta while at rest, 2 minutes after the onset of rapid atrial pacing, and 10 minutes after termination of pacing. Of 82 consecutive patients included in our study, 36 had stenosis of the left coronary artery, 12 had stenosis of the right coronary artery only, and 34 had no evidence of CAD. Samples taken at rest revealed no arteriovenous difference in platelet aggregation between patients with CAD and those without CAD. In patients with significant stenosis (> or = 50%) of the left coronary artery, atrial pacing caused platelet aggregation to increase in samples from the coronary sinus (64 +/- 9% increase; p < 0.01) but not in blood from the aorta (2 +/- 8% decrease; difference not significant). This increase was transient, with aggregation returning almost to resting values 10 minutes after pacing ended. Atrial pacing elicited no change in platelet aggregation in samples from either the coronary sinus or aorta of patients with nonsignificant stenosis (< 50%) of the left coronary artery, patients with significant stenosis of the right coronary artery only, and patients free of CAD. Thus, under resting conditions, no evidence of platelet activation across the coronary bed was seen regardless of CAD status.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial viability in patients with chronic coronary artery disease. Comparison of 99mTc-sestamibi with thallium reinjection and [18F]fluorodeoxyglucose.

BACKGROUND: 99mTc-sestamibi and thallium imaging have similar accuracy when used for diagnostic purposes, but whether sestamibi provides accurate information regarding myocardial viability in patients with chronic coronary artery disease has not been established. Since there is minimal redistribution of sestamibi over time, it may overestimate nonviable myocardium in patients with left ventricular dysfunction, in whom blood flow may be reduced at rest. METHODS AND RESULTS: We studied 54 patients with chronic coronary artery disease with a mean ejection fraction of 34 +/- 14%. Patients underwent stress/redistribution/reinjection thallium tomography and, within a mean of 5 days, same-day rest/stress sestamibi imaging using the same exercise protocol and with patients achieving the same exercise duration. Of the 111 reversible thallium defects on either the redistribution or reinjection study, 40 (36%) were determined to be irreversible on the rest/stress sestamibi study, whereas only 3 of 63 irreversible thallium defects despite reinjection (5%) were classified to be reversible by sestamibi imaging. The concordance regarding reversibility of myocardial defects between thallium stress/redistribution/reinjection and same day rest/stress sestamibi studies was 75%. A subgroup of 25 patients also underwent positron emission tomography (PET) studies with 15O-labeled water and [18F]fluorodeoxyglucose (FDG) at rest after an oral glucose load. As in the overall group of 54 patients, there was concordance between thallium and sestamibi imaging regarding defect reversibility in 51 of 73 regions (70%). In the remaining 22 discordant regions (30%), 18 (82%) appeared irreversible by sestamibi imaging but were reversible by thallium imaging. Myocardial viability was confirmed in 17 of 18 regions, as evidenced by normal FDG uptake (10 regions) or FDG/blood flow mismatch (7 regions) on PET. These regions were present in 16 of the 25 patients studied (64%). We then explored methods to improve the sestamibi results. First, when the 18 discordant regions with irreversible sestamibi defects were further analyzed according to the severity of defects, 14 (78%) demonstrated only mild-to-moderate reduction in sestamibi activity (51% to 85% of normal activity), suggestive of predominantly viable myocardium, and the overall concordance between thallium and sestamibi studies increased to 93%. Second, when an additional 4-hour redistribution image was acquired in 18 patients after the injection of sestamibi at rest, 6 of 16 discordant irreversible regions (38%) on the rest/stress sestamibi study became reversible, thereby increasing the concordance between thallium and sestamibi studies to 82%. CONCLUSIONS: These data indicate that same-day rest/stress sestamibi imaging will incorrectly identify 36% of myocardial regions as being irreversibly impaired and nonviable compared with both thallium redistribution/reinjection and PET. However, the identification of reversible and viable myocardium can be greatly enhanced with sestamibi if an additional redistribution image is acquired after the rest sestamibi injection or if the severity of reduction in sestamibi activity within irreversible defects is considered.

Complexes of nitric oxide with nucleophiles as agents for the controlled biological release of nitric oxide: antiplatelet effect.

Nitric oxide (NO) inhibits platelet aggregation. Accordingly, we hypothesized that complexes of diethylamine and spermine with NO (DEA/NO and SPER/NO, respectively), two vasodilators previously shown to release NO spontaneously in aqueous solution, may also be useful antiplatelet agents. Platelet aggregation was measured in whole blood or platelet-rich plasma by impedance aggregometry after addition of collagen. In whole blood, the dose response curve for DEA/NO added 1 min before collagen was similar to that for aspirin (60% inhibition at 10(-4) M), while SPER/NO and sodium nitroprusside were less potent by an order of magnitude. In platelet-rich plasma, 10(-6) M DEA/NO caused 60% inhibition, while SPER/NO and sodium nitroprusside were as active only at 10(-5) M; aspirin's potency was unchanged from that in whole blood. In vivo, DEA/NO and sodium nitroprusside produced significant platelet inhibition 1 min after intravenous injection in the rabbit at 50 nmol/kg. Similar in vivo platelet inhibition was observed with SPER/NO and aspirin, but only at higher dose. The effects of DEA/NO and sodium nitroprusside were transient, lasting less than 30 min after treatment, while the activity of SPER/NO and aspirin was sustained throughout the 30 min experiment. The magnitude and duration of the antiplatelet effects of DEA/NO and SPER/NO correlate with the rates at which they release nitric oxide spontaneously in aqueous solution. Thus, NO/nucleophile complexes merit further exploration both as research tools and as potential antiplatelet agents.

Angiogenic effects of low molecular weight heparin in patients with stable coronary artery disease: a pilot study.

OBJECTIVES: The study was designed to assess the feasibility of conducting a trial to investigate whether exercise and low molecular weight heparin therapy with dalteparin sodium (Fragmin) would improve collateral function to the ischemic myocardium in patients with coronary artery disease. BACKGROUND: The severity of myocardial ischemia in patients with coronary artery disease is at least partly dependent on the status of the collateral circulation. Therefore, improvement in collateral function would potentially provide a unique way of alleviating myocardial ischemia. Because the combination of ischemia and heparin has previously been demonstrated to enhance collateral growth, we studied the anti-ischemic effects of combined treatment with dalteparin sodium and exercise-induced ischemia in patients with coronary artery disease. METHODS: Twenty-three patients with stable coronary artery disease were randomized to receive either subcutaneous dalteparin sodium or placebo for a 4-week period. Patients received either placebo or 10,000 IU of dalteparin sodium by subcutaneous injection once daily for weeks 1 and 2 and 5,000 IU daily for weeks 3 and 4. During the 1st 2 weeks, patients were exercised to ischemia three times a day. At baseline and 4 weeks after treatment, treadmill exercise testing, exercise radionuclide ventriculography and 48-h ambulatory ST segment monitoring were performed. RESULTS: Eight (80%) of the 10 dalteparin sodium-treated patients compared with 4 (31%) of 13 placebo-treated patients (p < 0.02) had an increased rate-pressure product at the onset of 1 mm of ST segment depression. The duration of exercise to ischemia increased in all patients treated with low molecular weight heparin and in 62% of placebo-treated patients (p < 0.03). The number and duration of episodes of ST segment depression during ambulatory monitoring decreased by 30% and 35%, respectively (p < 0.05), in the dalteparin sodium group but were unchanged in the placebo group. The decrease in left ventricular ejection fraction with exercise was lower in 80% of dalteparin sodium-treated patients compared with 54% of placebo-treated patients (p = 0.06). When all five factors reflecting collateral function were considered together in a multivariate analysis of variance, there was a significant improvement in low molecular weight heparin-treated patients compared with placebo-treated patients (p = 0.014). CONCLUSIONS: This study provides preliminary evidence suggesting that exercise and low molecular weight heparin therapy with dalteparin sodium lessen myocardial ischemia and that the improvement is likely to be mediated by enhanced collateral function.

Complexes of nitric oxide with nucleophiles as agents for the controlled biological release of nitric oxide: hemodynamic effect in the rabbit.

Nitric oxide (NO) and drugs that generate NO are potent vasodilators. We investigated the in vivo vasodilator potential of a unique group of compounds that release NO spontaneously in solution, the NO/nucleophile complexes. The hemodynamic effects of diethylamine/NO complex (DEA/NO) (half-life < 3 min) and the spermine/NO complex (SPER/NO) (half-life > 30 min) administered intravenously were compared with those of sodium nitroprusside in anesthesized New Zealand white rabbits. Arterial pressure and systemic vascular resistance decreased, but central venous pressure, pulmonary arterial pressure, heart rate, and thermodilution cardiac output did not change in association with any of the three drugs in the doses administered. The hemodynamic effects were dose dependent. As predicted from their rates of spontaneous NO release, DEA/NO is a short-acting vasodilator with a duration similar to that of sodium nitroprusside, whereas SPER/NO is a longer-acting agent with a significant hypotensive effect 30 min after bolus injection. DEA/NO was equipotent to sodium nitroprusside, causing significant reductions in blood pressure and systemic vascular resistance at the lowest dose tested (1.5 nmol/kg). The data indicate that the NO/nucleophile complexes have predictable vasorelaxant effects in vivo as well as in vitro and suggest that their amenability to facile structure-reactivity and structure-activity modification should allow the design of NO donor drugs for a variety of applications in cardiovascular pharmacology.

Prognostic implications of myocardial ischemia during daily life in low risk patients with coronary artery disease.

OBJECTIVES: The purpose of this study was to determine the incidence and prognostic importance of myocardial ischemia detected by ambulatory monitoring in low risk, medically managed patients with coronary artery disease. BACKGROUND: Previous studies have demonstrated that certain high risk subsets of patients with coronary artery disease have improved survival with revascularization. The remaining low risk medically managed patients may still have episodes of silent ischemia during daily living, but the frequency and prognostic implications of such episodes in this group are unknown. METHODS: We prospectively studied the incidence and prognostic significance of ST segment changes recorded during daily activities in 116 asymptomatic or mildly symptomatic low risk patients with native coronary artery disease who were followed up for 29 +/- 13 months. Low risk patients were selected after excluding patients with 1) left main disease; 2) three-vessel coronary artery disease and left ventricular dysfunction at rest; 3) three-vessel disease and inducible ischemia during exercise; and 4) two-vessel disease, left ventricular dysfunction and inducible ischemia. RESULTS: Forty-five patients (39%) had transient episodes of ST segment depression during 48-h electrocardiographic (ECG) monitoring (total 217 episodes, lasting 7,223 min, 82% of episodes silent). There were eight acute cardiac events (seven myocardial infarctions, one episode of unstable angina) and nine patients underwent elective revascularization. Seven of the eight acute events occurred in patients without silent ischemia during monitoring. Kaplan-Meier survival analysis revealed no significant differences in event-free survival from either acute or total events in subgroups with or without silent ischemia during ambulatory ECG monitoring. None of the clinical, treadmill exercise, radionuclide ventriculographic or cardiac catheterization variables were predictive of outcome by Cox multivariate proportional hazard function analysis. Analysis of coronary arteriograms before and after acute cardiac events revealed that in five of the six patients studied, acute occlusion occurred in a coronary artery different from the artery with the severest stenosis on initial angiography. CONCLUSIONS: In patients categorized as at low risk on the basis of the results of cardiac catheterization and stress testing, silent myocardial ischemia during daily life was not uncommon, and its presence failed to predict future coronary events.

Endothelial dysfunction in patients with chest pain and normal coronary arteries.

BACKGROUND: A subgroup of patients with chest pain and angiographically normal epicardial coronary arteries have reduced dilator response to metabolic or pharmacological stimuli, but the mechanisms responsible for this reduced dilator response are unknown. In this study, we have investigated whether microvascular endothelial dysfunction is a cause of the observed reduced vasodilator reserve. METHODS AND RESULTS: The functional response of the microvasculature was studied with rapid atrial pacing at 150 beats per minute. Fifty-one patients, 20 hypertensive and 31 normotensive, with chest pain and normal epicardial coronary arteries (< 10% stenosis) were studied. Endothelial function was tested with incremental infusions of acetylcholine to achieve estimated intracoronary concentrations ranging from 10(-7) M to 10(-5) M. Endothelium-independent smooth muscle vasomotion was measured using intracoronary sodium nitroprusside. Endothelial dysfunction of epicardial coronary arteries, demonstrated as severe (> 50%) constriction with < 10(-5) M acetylcholine concentration, was evident in five patients (10%). In the remaining 46 patients, coronary blood flow increased with acetylcholine (mean, 78 +/- 43%) and atrial pacing (mean, 51 +/- 37%), and coronary vascular resistance decreased by 35 +/- 16% and 29 +/- 14%, respectively, but the responses were heterogeneous. There was a correlation between the coronary resistance change with acetylcholine and the change with atrial pacing: r = 0.68, p < 0.001 in these 46 patients. Thus, patients with depressed dilation with atrial pacing had reduced endothelium-dependent dilation with acetylcholine, and vice versa. However, the microvascular dilation caused by sodium nitroprusside was not significantly different between patients with and those without reduced dilation with atrial pacing, indicating that the vasodilator defect was not caused by smooth muscle dysfunction. There were no differences in the vasodilator responses with atrial pacing, acetylcholine, or nitroprusside between normotensive and hypertensive patients. Multivariate regression analysis was performed to determine whether age, sex, serum cholesterol level, hypertension, presence of mild epicardial vessel atherosclerosis, resting left ventricular function, change in left ventricular ejection fraction with exercise, vasodilation with acetylcholine, and vasodilation with sodium nitroprusside were independently related to the vasodilator response to atrial pacing. Only the change in coronary vascular resistance with acetylcholine was independently correlated with the change in resistance with atrial pacing: R2 = 0.46, p < 0.0001. CONCLUSIONS: Patients with chest pain, normal epicardial coronary arteries, and reduced vasodilation in response to atrial pacing appear to have associated endothelial dysfunction of the coronary microvasculature. Thus, microvascular endothelial dysfunction may contribute to the reduced vasodilator reserve with atrial pacing and anginal chest pain in these patients.

Role of increases in heart rate in determining the occurrence and frequency of myocardial ischemia during daily life in patients with stable coronary artery disease.

OBJECTIVES: The goal of this study was to investigate the role of increases in heart rate in the development of ischemic episodes recorded during ambulatory electrocardiographic (ECG) monitoring in patients with stable coronary artery disease and to establish the importance of such increases in determining the frequency of ambulatory myocardial ischemia. BACKGROUND: The factors that determine the occurrence and frequency of episodes of myocardial ischemia that patients with stable coronary artery disease experience during daily life have not been clearly defined. In particular, the role of increases in heart rate in the development of myocardial ischemia is controversial. METHODS: To address these issues, 54 patients (42 men and 12 women, mean age 60.5 +/- 8 years) with proved coronary artery disease who had > or = 1 mm ST segment depression during exercise testing underwent an exercise treadmill test with use of the National Institutes of Health combined protocol and a 48-h period of ambulatory ECG monitoring. The exercise ischemic threshold was determined as the heart rate at the onset of ST segment depression during exercise testing. RESULTS: During monitoring, 48 (89%) of the 54 patients had at least one episode of ST segment depression (mean +/- SD 6.6 +/- 5 episodes, range 0 to 22). The majority (320 of 359 or 89%) of ischemic episodes were preceded by an increase in heart rate > or = 10 beats/min; the most significant increase (22.3 +/- 10 beats/min) occurred during the 5-min period before the onset of the episode. An ischemic episode occurred 80% of the times the heart rate reached the exercise ischemic threshold. A strong correlation was observed between the number of times the exercise ischemic threshold was reached during monitoring and both the number and the duration of ischemic episodes (r = 0.90 and 0.71, respectively, p < 0.0001). CONCLUSIONS: Increases in heart rate that exceed the exercise ischemic threshold are commonly observed before the onset of episodes of ambulatory myocardial ischemia in patients with stable coronary artery disease. Moreover, such increases constitute an important determinant of the frequency of myocardial ischemia during daily life. These findings may explain the variability observed in the number of ischemic episodes and may have important implications for the mechanisms that contribute to myocardial ischemia in daily life and for the clinical evaluation of patients with coronary artery disease.

Platelet hyperaggregability across the coronary bed in response to rapid atrial pacing in patients with stable coronary artery disease.

BACKGROUND: Platelet aggregation is believed to contribute to the precipitation of acute ischemic syndromes. Because physical activity has been proposed as one possible trigger in converting a patient with chronic coronary artery disease to one with an acute ischemic syndrome, we examined the hypothesis that platelets become activated when coronary blood flow velocities (and thereby shear stress) increase across an atherosclerotic bed. METHODS AND RESULTS: During catheterization, 82 patients (36 with left coronary artery disease, 12 with only right coronary artery disease, and 34 with normal coronary arteries) had measurement of whole blood platelet aggregation performed on blood samples obtained simultaneously from the coronary sinus and aorta at rest, 2 minutes after onset of rapid atrial pacing, and 10 minutes after pacing was terminated. There was no arteriovenous difference in platelet aggregation under resting conditions in patients with versus those without coronary artery disease. Atrial pacing in patients with left coronary artery disease (greater than or equal to 50% stenosis in a major epicardial vessel) caused an increase in platelet aggregation in the coronary sinus blood (+64 +/- 9%, p less than 0.01) but not in arterial blood (2 +/- 8% decrease, p = NS). This increase was transient and returned nearly to baseline 10 minutes after termination of pacing. Patients with nonsignificant left coronary artery disease, those with normal coronary arteries, and patients with significant disease only in the right coronary artery (venous drainage not into the coronary sinus) did not show any changes in either the coronary sinus or arterial blood with atrial pacing. CONCLUSIONS: There is no evidence of platelet activation across a normal or an atherosclerotic coronary bed at rest. When coronary blood flow increases in the presence of significant (greater than or equal to 50%) narrowing of epicardial coronary arteries, however, platelets are activated and aggregate more easily. This mechanism may play a role in the precipitation of acute ischemic syndromes in patients with coronary artery disease.

Circadian variation in ischemic threshold. A mechanism underlying the circadian variation in ischemic events.

BACKGROUND: There is a circadian pattern in the occurrence of cardiac events in patients with coronary artery disease. Whether changes in coronary vascular tone contribute to these phenomena is unknown. We measured the ischemic threshold, defined as either the heart rate or rate-pressure product at 1-mm ST segment depression during treadmill exercise and used it as an index of the lowest coronary vascular resistance; the premise was that when ischemic threshold became lower, coronary vascular resistance was higher, and vice versa. METHODS AND RESULTS: Fifteen patients (group A) with stable coronary artery disease underwent four identical treadmill exercise tests in 24 hours, and ischemic threshold was measured as the heart rate at the onset of 1-mm ST depression. Before each treadmill test, postischemic forearm vascular resistance was measured after 5 minutes of forearm occlusion, using strain-gauge plethysmography. Sixteen additional patients (group B) underwent two treadmill tests at 8 AM and 1 PM, and ischemic threshold was measured as the heart rate-blood pressure product at 1-mm ST depression. A circadian variation was noted: In group A, the heart rate-derived ischemic threshold was lower at 8 AM and 9 PM compared with noon and 5 PM (p less than 0.03). Also, in group B, the rate-pressure product-derived ischemic threshold was 8 +/- 2% lower at 8 AM compared with 1 PM (p = 0.008). A circadian variation parallel to the observed variation in ischemic threshold was also noted in the postischemic forearm blood flow, which was lower in the morning and at night (p less than 0.004). There was a strong correlation between postischemic forearm blood flow and ischemic threshold (p less than 0.0001), such that ischemic threshold was lower at the time of day when postischemic forearm blood flow was lower, and vice versa. CONCLUSIONS: A lower ischemic threshold in the morning suggests that the ischemia-induced coronary vascular resistance is increased at this time, a finding supported by a similar variation in postischemic forearm vascular resistance. Parallel changes in forearm and coronary resistance suggest that generalized (neural or humoral factors) rather than local factors are responsible for the observed circadian changes. Increased coronary tone in the mornings may not only contribute to the higher incidence of transient ischemia but may help trigger acute cardiac events at this time.

Predictors of exercise benefit after operative relief of left ventricular outflow obstruction by the myotomy-myectomy procedure in hypertrophic cardiomyopathy.

To determine predictors of exercise benefit in patients with hypertrophic cardiomyopathy after operative relief of left ventricular (LV) outflow tract obstruction, 30 patients underwent catheterization and exercise testing before and 6 months after operation, and hemodynamic measurements were obtained. The increase in maximal oxygen consumption (VO2max) during treadmill exercise testing was chosen as an index of exercise benefit. Univariate analysis showed a significant positive correlation of operative change in VO2max with preoperative LV end-diastolic and pulmonary arterial wedge pressures, operative change in exercise duration, and operative reductions in LV end-diastolic and pulmonary arterial wedge pressures and resting LV outflow tract gradient, and a significant negative correlation with preoperative VO2max and percent predicted VO2max. Multivariate analysis by stepwise linear regression of only significant univariate variables selected only preoperative percent predicted VO2max, and operative reduction in LV end-diastolic pressure and resting LV outflow tract gradient as significant predictors of postoperative change in VO2max. Stepwise regression analysis, applied only to preoperative exercise and catheterization hemodynamic variables, selected only preoperative percent predicted VO2max and preoperative LV end-diastolic pressure as predictors of improvement in exercise capacity. Thus, patients with obstructive hypertrophic cardiomyopathy, after failing medical therapy, are most likely to demonstrate improvement in exercise capacity if preoperative exercise testing demonstrates limited exercise capacity and if surgery achieves reduction in elevated resting LV outflow tract gradients and LV filling pressures.