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Evaluate a web-based tailored nursing intervention, TAVIE en m@rche, on increasing daily steps after an acute coronary syndrome.Parallel two-group multicentre randomized trial.An experimental group receiving TAVIE en m@rche, was compared to a control group receiving hyperlinks to public websites. Acute coronary syndrome patients who were insufficiently active were recruited from three coronary care units. Daily steps at 12 weeks were the primary outcome. Secondary outcomes included self-reported walking and moderate to vigorous physical activity (MVPA). Exploratory outcomes were angina frequency, emergency department visits, hospitalizations and secondary prevention programme attendance.Primary data were analysed for 39 participants. No significant effects were found. At 12 weeks 275.9 more daily steps and 1,464.3 more energy expenditure in MVPA were found in the experimental group relative to the control. No effects were found for angina frequency, emergency department visits, hospitalizations and secondary prevention programme attendance.The lack of effect on our primary result may be explained by the intervention goal that was mismatched to the needs of our mostly sufficiently active sample at randomization, resulting in no meaningful change in daily steps. Although the non-significantly greater increase in self-reported MVPA may represent gains in health among the participants that accessed TAVIE en m@rche, this result should be interpreted with caution.From 40%-60% of acute coronary syndrome patients self-report insufficient levels of physical activity. No effect was found on the primary outcome of daily steps. Although not significant, a greater increase in MVPA was found at 12 weeks. The primary outcome can be explained by most of the sample having attained the physical activity recommendation at randomization. Caution in interpreting the non-significant increase in MVPA is warranted due to attrition bias and statistical uncertainty. Future directions may consider the timing of randomization in relation to meeting the needs of insufficiently active acute coronary syndrome patients.目的: 评估基于网络的定制护理干预(TAVIE en m@rche)对于急性冠脉综合征后增加每日行走步数的作用。 设计: 平行的两组多中心随机研究 方法: 对比接受TAVIE en m @ rche的实验组与接收公共网站超链接的对照组。我们从三个冠心病重症监护病房招募了活动不足的急性冠状动脉综合征患者。研究主要结果是12周的每日步数。次要结果包括患者自己报告的行走和中等强度到高强度的身体活动(MVPA)。探索性结果为心绞痛发作频率、急诊就诊、住院和二级预防方案出现次数。 结果: 我们分析了39名参与者的原始数据,没有发现显著影响。在十二周中,相比于对照组,实验组的中等强度到高强度的身体活动中,每日步数增加了275.9步,并且增加了1464.3的能量消耗。心绞痛发作频率、急诊就诊、住院和二级预防方案出现次数没有受到影响。 结论: 没有对主要结果产生影响的原因可能是干预目标与随机分配的多数活动充分的样本需求不匹配,导致每日步数没有出现有意义的变化。尽管患者自己报告的中等强度到高强度的身体活动并没有显著地大幅增长,这可能意味着访问TAVIE en m@rche的参与者健康状况有所改善,但是对于这一结果,应当谨慎解释。 影响: 40%至60%的急性冠状动脉综合征患者自己报告的身体活动不足。每日步行没有对主要结果产生影响。尽管不显著,但在十二周中,每日中等强度到高强度的身体活动有所增长。出现这样的主要结果的原因是,大多数样本在随机分组时已经得到了活动身体的建议。由于损耗性偏差和统计不确定性,对这一非显著增长,应当谨慎解释。今后的研究方向可能会考虑随机化的时间,以满足缺少身体活动的急性冠状动脉综合征患者的需求。.

Objective The American Heart Association has endorsed depression as a cardiac risk factor and recommends screening as part of routine practice. This has been met with controversy due to inconsistencies in the data linking depression treatment to better cardiovascular outcomes. Our objective was to prospectively assess the association between depression treatment (defined as being prescribed antidepressant medication) and major adverse cardiovascular events (MACE) in patients referred for exercise stress tests. Method Two thousand three hundred eighty-five consecutive patients presenting for myocardial perfusion exercise stress tests underwent a sociodemographic, medical, and psychiatric interview (Primary Care Evaluation of Mental Disorders [PRIME-MD]) and completed the Beck Depression Inventory (BDI). History of cardiovascular disease (CVD) and antidepressant use was self-reported and verified via chart review. Participants followed over an 8.8-year follow up, and information regarding MACE incidence (including cardiac mortality, nonfatal myocardial infarction, revascularization procedures, cerebrovascular events) was obtained from provincial administrative databases. Results 8% (n = 190) of the sample were taking antidepressants at baseline, 41% (n = 916) had a history of CVD, and 38.7% (n = 921) had depression according to the PRIME-MD or BDI. Antidepressant treatment was associated with a 30% reduced risk of MACE (Hazard ratio [HR] = 0.697; 95% confidence interval [CI] = [0.504, 0.964]; p = .029). A 46% reduction in risk was associated with antidepressant treatment among those without CVD (HR = 0.542; 95% CI [0.299, 0.981]; p = .043). In depressed patients, a 33% reduction in risk of MACE associated with antidepressant use was seen (adjusted HR = 0.674; 95% CI [0.440, 1.033]; p = .07). Conclusions Antidepressants may be cardio-protective among patients presenting for stress testing independent of risk factors including CVD and depression. Results support treating depression with antidepressants in this population to reduce risk of MACE. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Antiplatelet therapy (APT) has become an important tool in the treatment and prevention of atherosclerotic events, particularly those associated with coronary artery disease. A large evidence base has evolved regarding the relationship between APT prescription in various clinical contexts and risk/benefit relationships. The Guidelines Committee of the Canadian Cardiovascular Society and Canadian Association of Interventional Cardiology publishes regular updates of its recommendations, taking into consideration the most recent clinical evidence. The present update to the 2011 and 2013 Canadian Cardiovascular Society APT guidelines incorporates new evidence on how to optimize APT use, particularly in situations in which few to no data were previously available. The recommendations update focuses on the following primary topics: (1) the duration of dual APT (DAPT) in patients who undergo percutaneous coronary intervention (PCI) for acute coronary syndrome and non-acute coronary syndrome indications; (2) management of DAPT in patients who undergo noncardiac surgery; (3) management of DAPT in patients who undergo elective and semiurgent coronary artery bypass graft surgery; (4) when and how to switch between different oral antiplatelet therapies; and (5) management of antiplatelet and anticoagulant therapy in patients who undergo PCI. For PCI patients, we specifically analyze the particular considerations in patients with atrial fibrillation, mechanical or bioprosthetic valves (including transcatheter aortic valve replacement), venous thromboembolic disease, and established left ventricular thrombus or possible left ventricular thrombus with reduced ejection fraction after ST-segment elevation myocardial infarction. In addition to specific recommendations, we provide values and preferences and practical tips to aid the practicing clinician in the day to day use of these important agents.

Objectives The present study aims to document the problem of suicidality in emergency department (ED) patients with unexplained chest pain and to assess the strength and independence of the relationship between panic and suicidal ideation (SI) in this population. Method This cross-sectional study included 572 ED patients with unexplained chest pain. SI, history of suicide attempts, history of SI and the presence of thoughts about how to commit suicide were assessed. Logistic regression analyses were used to quantify the relationship between current SI and panic. Results Approximately 15% [95% confidence interval (CI), 12%–18%] of patients reported current SI, and 33% (95% CI, 29%–37%) reported history of SI. Nearly 19% (95% CI, 16%–22%) of patients had thought about a method to commit suicide, and 33% (95% CI, 29%–37%) had a history of a suicide attempt. Panic attacks were diagnosed in 42% (95% CI, 38%–46%) of patients, and 45% (95% CI, 39%–51%) of those had panic disorder. Panic increased the crude likelihood of current SI [odds ratio (OR)=2.53, 1.4–4.5]. This increase in SI risk remained significant after controlling for confounding factors (OR=1.70, 95% CI, 1.0–2.9). Conclusions Suicidality and SI were common and often severe in our sample of ED patients with unexplained chest pain.

Purpose This study aimed at (1) establishing the prevalence of paniclike anxiety in emergency department (ED) patients with unexplained chest pain (UCP); (2) describing and comparing the sociodemographic, medical, and psychiatric characteristics of UCP patients with and without paniclike anxiety; and (3) measuring the rate of identification of panic in this population. Basic Procedure A structured interview, the Anxiety Disorders Interview Schedule for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition , was administered to identify paniclike anxiety and evaluate patients' psychiatric status. Anxious and depressive symptoms were evaluated with self-report questionnaires. Medical information was extracted from patients' medical records. Main Findings The prevalence of paniclike anxiety was 44% (95% CI, 40%-48%) in the sample (n = 771). Psychiatric disorders were more common in panic patients (63.4% vs 20.1%), as were suicidal thoughts (21.3% vs 11.3%). Emergency physician diagnosed only 7.4% of panic cases. Principal Conclusions Paniclike anxiety is common in ED patients with UCP, and this condition is rarely diagnosed in this population.

Background: Several patient characteristics have been shown to increase the risk of inadequate platelet inhibition by aspirin, yet underlying mechanisms remain mostly unknown. We explored whether oxidative stress, via isoprostane formation, was associated with inadequate platelet response to aspirin. Additionally, we sought to investigate whether individual pre-selected demographic, hematological or biochemical parameters further increased the risk of inadequate platelet response to aspirin. Methods: Two hundred consecutive subjects suffering from stable coronary artery disease and under daily aspirin therapy were enrolled in our study. Inadequate platelet response to aspirin was defined as residual platelet aggregation ≥20% per arachidonic acid-induced light transmission aggregometry. Morning urinary samples were used to determine levels of isoprostanes (8-iso-PGF2α) using an enzyme immunoassay. Results: Eight subjects were deemed to present inadequate platelet response to aspirin. Wide intersubject variability was observed in urinary 8-iso-PGF2α levels. However, levels were similar between aspirin responders and non-responders. Patients with inadequate platelet response to aspirin had higher platelet counts and received the lowest daily aspirin dose when compared to responders, suggesting subtherapeutic aspirin therapy due to increased platelet production. Only platelet count remained independently predictive of inadequate platelet response to aspirin in a multiple logistic regression model. Conclusions: Urinary 8-iso-PGF2α levels, a reflection of systemic oxidative stress, did not appear to contribute to impaired platelet responsiveness to aspirin, while increased platelet production may partly explain this phenomenon. © 2009 Elsevier Ireland Ltd. All rights reserved.

Hyporesponsiveness to antiplatelet agents has been linked to an increased risk of major adverse cardiovascular events. However, light transmission aggregometry (LTA), the gold standard methodology for assessing platelet function, requires expertise and is labour-intensive, which render its use in clinical settings impractical. We assessed whether platelet count drop (PCD), a technique widely available in any haematology laboratory, could replace LTA in testing for inhibition of platelet aggregation induced by antiplatelet agents.One hundred and sixty-one coronary artery disease patients taking aspirin alone and 91 patients taking a combination of aspirin and clopidogrel were enrolled. Platelet aggregation was measured by LTA and PCD stimulated with 1.6 mM of arachidonic acid (AA) for aspirin and 5 and 20 microM of adenosine diphosphate (ADP) for clopidogrel.Correlation between AA-induced LTA and PCD was nonexistent (r=-0.043, p=0.587), while correlation between ADP-induced LTA and PCD was low (r=0.374, p0.0001 for ADP 5 microM and r=0.402, p0001 for ADP 20 microM ). PCD, whether stimulated with AA or ADP, overestimated platelet aggregation as assessed by LTA, by 13-18%. The wide 95% limits of agreement suggest that the assays can disagree significantly in individual patients.Although the PCD method is widely available in non-specialized laboratories, our results demonstrate that there is poor correlation with the current gold standard, i.e. LTA. Thus, PCD should not be used in replacement of LTA to assess antiplatelet responsiveness.

Background: Adequate platelet inhibition before percutaneous coronary intervention (PCI) reduces periprocedural and long-term ischemic complications. Reduced response to clopidogrel has been associated with subsequent major adverse cardiovascular events. Strategies to optimize platelet inhibition pre-PCI are under investigation. This study evaluated the effect on platelet aggregation of four different dosing regimens of clopidogrel given before elective PCI in a randomized, prospective, double-blind, and placebo-controlled design. Methods: One hundred twenty participants were randomized to one of four groups of clopidogrel: (a) 300 mg on the day prior to angiography; (b) 600 mg on the day prior to angiography; (c) 300 mg followed by 75 mg daily started 1 week prior to angiography; and (d) 300 mg followed by 150 mg daily started 1 week prior to angiography. Platelet aggregation was assessed by light transmission aggregometry (LTA) after stimulation with adenosine diphosphate 20 μM at baseline and at the time of diagnostic coronary angiography. The absolute change in platelet aggregation between these two time points was considered the main outcome measure. Results: At the time of diagnostic coronary angiography, the 300-mg/150-mg daily regimen achieved the greatest decrease in platelet aggregation (37 ± 19%), while the 300 mg regimen provided the smallest (20 ± 22%), an absolute difference between the two groups of 17.2 ± 5.1% (P = 0.005). Conclusions: A 300-mg loading dose of clopidogrel followed by 150 mg daily for 1 week prior to coronary angiography provides more effective platelet inhibition, as defined by LTA, compared to the standard 300-mg loading dose regimen at the time of coronary intervention.

Variable biological effect of aspirin is suggested to be related to pharmacological resistance. The incidence of this so-called "resistant" state varies with the study population and the assay used. We determined performance features of five assays used to assess aspirin effects in non-smoking healthy volunteers not taking any drug known to interfere with platelet function. Blood and urine samples were obtained immediately before and after 8-10 days of aspirin 80 mg intake. Forty-five participants 19-59 years old were enrolled. The sensitivity (SE), specificity (SP), and optimal cut-off (CO) value to detect the effect of aspirin were: light transmission aggregometry (LTA) with 1.6 mM arachidonic acid (AA) - SE 100%, SP 95.9%, CO 20%; LTA with adenosine diphosphate (ADP) 10 microM - SE 84.4%, SP 77.8%, CO 70%; VerifyNow Aspirin - SE 100%, SP 95.6%, CO 550 ARU; platelet count drop - SE 82.2%, SP 86,7%, CO 55%; TEG((R)) - SE 82,9%, SP 75,8%, CO 90%; and urinary 11-dehydrothromboxane B(2) levels (11-dHTB(2)) - SE 62.2%, SP 82.2%, CO 60 pg/ml. AA-induced LTA and the VerifyNow assay reliably detected aspirin intake in all subjects; there was wide overlap in pre- and post- aspirin results with ADP-induced LTA, platelet count drop, TEG((R)) and urinary 11-dHTB(2) assays. These results suggest that some of the variability in the reported incidence of "aspirin resistance" is unrelated to aspirin intake but related to inherent limitations of some assays to detect aspirin mediated effects or to underlying platelet reactivity variability independent of aspirin-mediated cyclooxygenase-1 inhibition.

The emergence of point-of-care assays enabling bedside testing such as the VerifyNow P2Y12 system might prove useful in clinical settings. The aim of this study was to evaluate the ability of the VerifyNow P2Y12 assay to estimate the inhibition of platelet aggregation provided by clopidogrel in the absence of baseline off-drug aggregation data. Sixty-eight patients with coronary artery disease scheduled to initiate clopidogrel therapy underwent platelet aggregation testing by VerifyNow P2Y12 at baseline and after clopidogrel administration. The inhibition reported by the VerifyNow assay (relative to thrombin receptor activating peptide-induced platelet aggregation, serving as baseline) was compared with that calculated with the actual adenosine diphosphate-induced baseline obtained with the same methodology. The postclopidogrel thrombin receptor activating peptide-induced aggregation showed a great discordance with that induced by adenosine diphosphate before clopidogrel with a bias of 24 units (95% limits of agreement from -142 to 190 units). Moreover, the inhibition reported by the assay overestimated the standard before-and-after testing data by an average of 8% (95% limits of agreement from -49% to 65%), making its use without a true baseline comparator unsatisfactory. The VerifyNow P2Y12 assay fails to accurately quantify platelet inhibition achieved by clopidogrel compared with before-and-after testing. Further studies are required to establish the clinical usefulness of the VerifyNow P2Y12 assay to accurately predict the occurrence of major adverse cardiovascular events in patients with reduced clopidogrel efficacy before it can be implemented in clinical practice. At present, the use of this assay in clinical care cannot be recommended for monitoring clopidogrel therapy.

Background— Women diagnosed with coronary artery disease (CAD) typically experience worse outcomes relative to men, possibly through diagnosis and treatment delays. Reasons for these delays may be influenced by mood and anxiety disorders, which are more prevalent in women and have symptoms (eg, palpitations and fatigue) that may be confounded with CAD. Our study examined sex differences in the association between mood and anxiety disorders and myocardial ischemia in patients with and without a CAD history presenting for exercise stress tests. Methods and Results— A total of 2342 patients (women n=760) completed a single photon emission computed tomographic exercise stress test (standard Bruce Protocol) and underwent a psychiatric interview (The Primary Care Evaluation of Mental Disorders) to assess mood and anxiety disorders. Ischemia was assessed using single photon emission computed tomography, with odds ratio used to calculate the effect of sex and mood/anxiety on the presence of ischemia during stress testing by CAD history in a stratified analyses, adjusted for relevant covariates. There was a sex by anxiety interaction with ischemia in those without a CAD history ( P =0.015): women with anxiety were more likely to exhibit ischemia during exercise than women without anxiety (odds ratio, 1.75; 95% confidence interval, 1.05–2.89). No significant effects were observed for men nor mood. Conclusions— Women with anxiety and no CAD history had higher rates of ischemia than women without anxiety. Results suggest that anxiety symptoms, many of which overlap with those of CAD, might mask CAD symptoms among women (but not men) and contribute to referral and diagnostic delays. Further research is needed to confirm this hypothesis.

Aims We sought to compare the results obtained from six major platelet function tests in the assessment of the prevalence of aspirin resistance in patients with stable coronary artery disease. Methods and results 201 patients with stable coronary artery disease receiving daily aspirin therapy (≥80 mg) were recruited. Platelet aggregation was measured by: (i) light transmission aggregometry (LTA) after stimulation with 1.6 mM of arachidonic acid (AA), (ii) LTA after adenosine diphosphate (ADP) (5, 10, and 20 µM) stimulation, (iii) whole blood aggregometry, (iv) PFA-100®, (v) VerifyNow Aspirin®; urinary 11-dehydro-thromboxane B2 concentrations were also measured. Eight patients (4%, 95% CI 0.01–0.07) were deemed resistant to aspirin by LTA and AA. The prevalence of aspirin resistance varied according to the assay used: 10.3–51.7% for LTA using ADP as the agonist, 18.0% for whole blood aggregometry, 59.5% for PFA-100®, 6.7% for VerifyNow Aspirin®, and finally, 22.9% by measuring urinary 11-dehydro-thromboxane B2 concentrations. Results from these tests showed poor correlation and agreement between themselves. Conclusion Platelet function tests are not equally effective in measuring aspirin's antiplatelet effect and correlate poorly amongst themselves. The clinical usefulness of the different assays to classify correctly patients as aspirin resistant remains undetermined.

ST-segment depression is commonly seen in patients with acute coronary syndromes. Most authors have attributed it to transient reductions in coronary blood flow due to nonocclusive thrombus formation on a disrupted atherosclerotic plaque and dynamic focal vasospasm at the site of coronary artery stenosis. However, ST-segment depression was never reproduced in classic animal models of coronary stenosis without the presence of tachycardia. We hypothesized that ST-segment depression occurring during acute coronary syndromes is not entirely explained by changes in epicardial coronary artery resistance and thus evaluated the effect of a slow, progressive epicardial coronary artery occlusion on the ECG and regional myocardial blood flow in anesthetized pigs. Slow, progressive occlusion over 72 min (SD 27) of the left anterior descending coronary artery in 20 anesthetized pigs led to a 90% decrease in coronary blood flow and the development of ST-segment elevation associated with homogeneous and transmural myocardial blood flow reductions, confirmed by microspheres and myocardial contrast echocardiography. ST-segment depression was not observed in any ECG lead before the development of ST-segment elevation. At normal heart rates, progressive epicardial stenosis of a coronary artery results in myocardial ischemia associated with homogeneous, transmural reduction in regional myocardial blood flow and ST-segment elevation, without preceding ST-segment depression. Thus, in coronary syndromes with ST-segment depression and predominant subendocardial ischemia, factors other than mere increases in epicardial coronary resistance must be invoked to explain the heterogeneous parietal distribution of flow and associated ECG changes.

We sought to evaluate the impact of a continuous intravenous infusion of perflutren on systemic pulmonary artery pressures at clinically relevant doses for myocardial perfusion imaging in pigs.Five anesthetized, ventilated, open-chest pigs were administered perflutren intravenously at a rate of 0.0364 mL/kg/min over approximately 5 minutes.Optimal, sustained myocardial opacification was achieved in all animals. Perflutren produced transient, reversible increases in pulmonary artery pressures versus baseline: 10.6% (3.0 +/- 1.4 mm Hg; 95% confidence interval 1.7-4.2; P.01) for systolic, 15.2% (2.5 +/- 1.4 mm Hg; 95% confidence interval 1.3-3.7; P.05) for diastolic, and 11.6% (2.6 +/- 1.1 mm Hg; 95% confidence interval 1.68-3.65; P.01) for mean pressures. Heart rate and systemic arterial pressures displayed nonsignificant increases during perflutren infusion compared with baseline.A continuous intravenous infusion of perflutren at a rate achieving optimal, sustained myocardial perfusion imaging in pigs induces a mild, transient, not clinically significant increase in pulmonary artery pressures without affecting heart rate or systemic arterial pressures.

Objectives This study evaluates the impacts of seasonal and lunar cycles on anxiety and mood disorders, panic and suicidal ideation in patients consulting the emergency department (ED) with a complaint of unexplained chest pain (UCP). Methods Patients with UCP were recruited from two EDs. Psychiatric diagnoses were evaluated with the Anxiety Disorders Interview Schedule for DSM-IV. Results Significant seasonal effects were observed on panic and anxiety disorders, with panic more frequently encountered during spring [odds ratio (OR)=1.378, 95% confidence interval (CI)=1.002–1.896] and anxiety disorders during summer (OR=1.586, 95% CI=1.037–2.425). Except for one significant finding, no significant effects of lunar cycles were observed. These findings encourage ED professionals and physicians to abandon their beliefs about the influence of lunar cycles on the mental health of their patients. Such unfounded beliefs are likely to be maintained by self-fulfilling prophecies.

Study Objective. To evaluate the effect of tirofiban (a glycoprotein IIb-IIIa inhibitor) in preventing streptokinase-induced, antibody-mediated platelet aggregation after administration of streptokinase or development of a streptococcal infection. Design. Prospective analysis. Setting. Research center of a Canadian hospital. Participants. Forty-five healthy volunteers, 45 patients who had received streptokinase within the past 3 years, and 13 patients who had a severe streptococcal infection also within the past 3 years. Intervention. Blood samples were drawn to measure the extent of inhibition of streptokinase-induced, antibody-mediated platelet activation and aggregation by tirofiban. Measurements and Main Results. Platelet aggregation was measured by using a turbidimetric method. The extent of inhibition by tirofiban was measured by incubating tirofiban for 2 minutes before adding streptokinase 5000 U/ml. Also, tirofiban was added 2 minutes before adding adenosine 5′-diphosphate (ADP) 2 μM/L into the last tube as a comparison. Streptokinase-induced, antibody-mediated platelet aggregation was observed in 10 (22%) of the 45 patients treated with streptokinase, in 3 (23%) of the 13 patients with streptococcal infection, and in none of the 45 healthy volunteers. Tirofiban inhibited streptokinase-induced, antibody-mediated platelet aggregation by 89 ± 14% (p

Streptokinase use, in acute myocardial infarction, is hindered by failure to reperfuse (60%) and early reocclusion (16%). This phenomenon may, among other causes, be due to systemic inactivation of streptokinase, as well as streptokinase-induced platelet aggregation and clot propagation from antibodies to streptokinase produced after streptokinase administration or streptococcal infections. The purpose of this study was to determine the incidence of streptokinase-induced, antibody-mediated, platelet activation and aggregation after administration of SK or development of a streptococcal infection.We included 45 normal volunteers (Control group), as well as 45 patients who had received streptokinase (Streptokinase group) and 13 who had suffered a severe streptococcal infection (Streptococcal infection group) within the past 3 years. Extent of streptokinase-induced, antibody-mediated, platelet activation and aggregation, as well as anti-streptokinase antibody and streptokinase resistance titers (lowest streptokinase concentration to cause clot lysis within 10 min) were measured.Whereas streptokinase-induced, antibody-mediated, platelet activation was observed in 49% of streptokinase patients and in only 17% and 15% of streptococcal infection patients and normal volunteers (p0.05 Streptokinase vs. Control and Streptokinase vs. Streptococcal infection), streptokinase-induced platelet aggregation was observed in 23% of streptokinase patients and streptococcal infection patients, and in none of the control patients (p0.05).Streptokinase-induced, antibody-mediated, platelet activation and aggregation occur in patients with high titers of anti-streptokinase antibody and may play a role in failure of streptokinase therapy. Streptococcal infection patients behave like streptokinase patients in terms of the reactivity of their platelets to subsequent streptokinase dose in vitro.

Epidemiological studies have linked clopidogrel discontinuation with an increased incidence of ischemic events. This has led to the hypothesis that clopidogrel discontinuation may result in a pharmacological rebound. We evaluated the impact of clopidogrel discontinuation on platelet function. Platelet aggregation was measured by light transmission aggregometry (LTA) in response to adenosine diphosphate (ADP) 0.5, 1, 1.5, 2.5, 5 and 10 µM and by VerifyNow® P2Y12, in 37 clinically stable coronary artery disease (CAD) patients scheduled to discontinue clopidogrel treatment, and 37 clinically stable CAD patients not taking clopidogrel. Platelet function was assessed the day before clopidogrel cessation and 1, 3, 7, 14, 21 and 28 days after. Clopidogrel had been initiated a median of 555 days (ranging from 200 to 2280 days) before the treating cardiologist recommended its discontinuation. All participants were taking aspirin, most commonly 80 mg daily although a minority was prescribed 325 mg daily. Following clopidogrel discontinuation, VerifyNow® P2Y12 did not detect any rebound platelet activity, but ADP-induced LTA showed platelet sensitization to ADP, particularly at low ADP levels. Increased platelet activity was detectable seven days after clopidogrel cessation and remained higher than in controls 28 days after discontinuation. No clinical event occurred in any of the participants during the 28 days following clopidogrel cessation. In conclusion, platelet sensitization to ADP as a consequence of chronic clopidogrel administration may partially explain the recrudescence of ischemic events following clopidogrel discontinuation in otherwise stable coronary artery patients.

Objective To document the prevalence and characteristics of nonfearful panic attacks (NFPA) and their consequences on panic identification and access to mental health services in patients with noncardiac chest pain. Method This cross-sectional sample included 339 patients with noncardiac chest pain and panic attacks. A structured interview was used to collect data on panic attacks, psychiatric morbidity, sociodemographic variables, and previous consultations with a psychiatrist or psychologist. Medical files were reviewed to assess the rate of NFPA identification in the emergency department. Results In our sample of patients with noncardiac chest pain, 39% of those with panic attacks reported NFPA. Psychiatric morbidity was lower in patients with NFPA than in patients with typical panic attacks (49.6% vs 71.1%), as was the mean number of panic symptoms (6 vs 7.8). The rate of panic attack identification was similar in both the groups, but patients with NFPA were less likely to have consulted a psychiatrist or psychologist during their lifetime (34% vs 46%). Conclusions NFPA were highly prevalent in our sample of emergency department patients with noncardiac chest pain. NFPA is associated with significant psychiatric morbidity but these patients were less likely to follow through with referral to a psychiatrist or psychologist than patients with typical panic attacks were.

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.

Objectives The current study was designed (1) to assess insomnia symptoms and sleep-related beliefs in a population of patients presenting in emergency department with unexplained chest pain (UCP) and (2) to examine the associations between insomnia and pain. Methods This is a report of secondary data from a cross-sectional study performed in the emergency department of 2 academic hospitals. Patients with UCP seen in an emergency department were assessed using sleep questionnaires and the Anxiety Disorders Interview Schedule for Diagnostic and Statistical Manual of Mental Disorders, fourth edition . Results Nearly every second patient with UCP (44%) seen in an emergency department suffered from clinically significant insomnia symptoms. Most patients with an anxiety or a mood disorder had insomnia, but a minority of patients with insomnia had an anxiety or a mood disorder. Insomniacs with an anxiety disorder were similar to insomniacs without comorbid anxiety for sleep-related beliefs and depressive symptoms, and both groups of insomniacs reported more depressive symptoms and faulty beliefs than both groups of good sleepers, i.e., either with or without an anxiety disorder. Results from regression analyses revealed that insomnia was associated with pain on univariate regression analysis and accounted for 1.3% of the variance in both pain intensity and interference. However, this association was rendered nonsignificant when additional variables were added to the model. Conclusions Insomnia symptoms are an important, but often disregarded, feature present in a significant proportion of patients with UCP. As insomnia showed stronger associations with pain than anxiety or depression, it may represent an important factor contributing to the development and recurrence of UCP.

SummaryHigh on-treatment platelet reactivity (HPR) has been identified as an independent risk factor for ischaemic events. The randomised, doubleblind, 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 metaboliser [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.

Limited data exist regarding the management of patients with acute coronary syndrome (ACS) in high-income countries compared with low/middle-income countries. We aimed to compare in-hospital trends of revascularization and prescription of medications at discharge in patients with ACS from high-income (Canada and United States) and low/middle-income (India, Iran, Pakistan, and Tunisia) countries. Data from a double-blind, placebo-controlled, randomized trial investigating the effect of bupropion on smoking cessation in patients after an enzyme-positive ACS was used for our study. A total of 392 patients, 265 and 127 from high-income and from low/middle-income countries, respectively, were enrolled. Patients from high-income countries were older, and were more likely to have diagnosed hypertension and dyslipidemia. During the index hospitalization, patients from high-income countries were more likely to be treated by percutaneous coronary intervention (odds ratio [OR] 19.7, 95% confidence interval [CI] 10.5 to 37.0). Patients with ST elevation myocardial infarction from high-income countries were more often treated by primary percutaneous coronary intervention (OR 16.3, 95% CI 6.3 to 42.3) in contrast with thrombolytic therapy (OR 0.24, 95% CI 0.14 to 0.41). Patients from high-income countries were also more likely to receive evidence-based medications at discharge (OR 2.32, 95% CI 1.19 to 4.52, a composite of aspirin, clopidogrel, and statin). In conclusion, patients with ACS in low/middle-income countries were less likely to be revascularized and to receive evidence-based medications at discharge. Further studies are needed to understand the underutilization of procedures and evidence-based medications in low/middle-income countries.

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.

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.

The objective was to demonstrate the derivation and the preliminary validation of a brief screening score to improve recognition of panic-like anxiety in emergency department (ED) patients with unexplained chest pain.This cross-sectional study included 507 ED patients with unexplained chest pain randomly assigned to the derivation condition (n = 201) or the validation condition (n = 306). The Anxiety Disorders Interview Schedule for DSM-IV (ADIS-IV) acted as the criterion standard for panic diagnosis. Receiver operating characteristic (ROC) curves were used to determine which of the sociodemographic, medical, and questionnaire response variables best predicted the presence of panic-like anxiety in the derivation condition. The selected predictors were entered in a logistic regression analysis to determine variables to be included in the screening score. The predictive validity of the resulting score was evaluated in both conditions.The four-item Panic Screening Score (PSS) identified panic-like anxiety with a sensitivity of 63% (95% confidence interval [CI] = 52% to 73%) and a specificity of 84% (95% CI = 76% to 90%) in the derivation phase. The positive predictive value was 74% (95% CI = 62% to 93%) and the negative predictive value was 76% (95% CI = 68% to 89%). In the validation phase, the sensitivity and specificity were 53% (95% CI = 44% to 62%) and 85% (95% CI = 78% to 89%), respectively. The positive predictive value was 72% (95% CI = 62% to 80%) and the negative predictive value was 71% (95% CI = 65% to 77%).The PSS may be useful to identify patients with unexplained chest pain who could benefit from referral to mental health professionals or their primary care providers for evaluation of panic attack and panic disorder. Prospective studies to improve and validate the PSS, followed by impact analysis, are mandatory before clinical implementation.

The aim of our study was to compare the electrocardiographic recordings in an experimental open-chest swine model before and after left-sided thoracotomy to detect any surgery-induced fluctuations that might interfere with subsequent experimental interventions. We obtained electrocardiograms from 8 deeply anesthetized domestic swine and compared the respective ST-segment potentials obtained after vascular surgery and after left-sided thoracotomy and dissection of the left anterior descending coronary artery. Compared with baseline recordings, no significant ST-segment deviation on any of the electrocardiographic leads occurred after vascular surgery. However, statistically significant ST-segment depression was observed after thoracotomy. Invasive surgical procedures in open-chest swine models may lead to morphologic changes in the ST segment. The physiologic mechanism of these changes is not fully understood.

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 electrocardiographie (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 mullivariate 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.

Introduction Intersubject variability in platelet response to aspirin could be related to genetic factors that regulate platelet enzymes or receptors. This study evaluates the impact of the selected polymorphisms in the COX-1 gene, the CYP5A1 gene, the P2RY1 receptor gene, and the GPIIbIIIa receptor gene on platelet response to aspirin and risk of suffering from major adverse cardiovascular and cerebrovascular events (MACCE). Materials and methods 192 Caucasian patients with stable coronary artery disease treated with daily aspirin were recruited and followed for 3 years. Platelet aggregation was measured by light transmission aggregometry with arachidonic acid (1.6 mM) and adenosine diphosphate (5, 10 or 20 μM) used as agonists. Genotyping was performed by standard PCR methods. Results Arachidonic acid-induced platelet aggregation was unaffected by the COX-1 22C/T and by the PlA1/A2 polymorphisms. However, carriers of the 1622 G/G genotype of the P2RY1 gene had significantly higher levels of arachidonic acid-induced platelet aggregation compared with non-carriers (AA 2.0%, AG 2.0% vs. GG 9.0%, p = 0.047). Carrying the 1622 G/G genotype increased the risk of inadequate platelet response to aspirin, defined as arachidonic acid-induced aggregation ≥ 20%, by a factor of 8.5 (1.4 – 53.3, p = 0.022) and the risk of 3-year MACCE by a factor of 7 (1.4 – 34.7, p = 0.017). Conclusion The 1622A/G mutation of the P2RY1 gene could contribute to inadequate platelet response to aspirin and is associated with an increased risk of suffering from MACCE.

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.

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.

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.

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.

The prognostic value of radionuclide measures of left ventricular function at rest and exercise is well established. Some studies have suggested that the frequency and duration of silent ischemia during ambulatory monitoring provide similar prognostic information; however, studies comparing these two techniques have not been performed. This study examines the relation between left ventricular function at rest and exercise-induced ischemia assessed by radionuclide ventriculography with myocardial ischemia during ambulatory electrocardiographic (ECG) monitoring. Of the 155 patients with coronary artery disease studied, 88% had left ventricular dysfunction with exercise, defined as failure of the ejection fraction to increase by greater than 4% with exercise, and 33% of patients had left ventricular dysfunction at rest (ejection fraction less than 45%); 52% had transient episodes of ST segment depression during 48-h ambulatory ECG monitoring. Exercise-induced left ventricular dysfunction during radionuclide ventriculography was extremely sensitive (94%) in detecting patients with ischemic episodes during ambulatory ECG monitoring; however, only 55% of patients with exercise-induced left ventricular dysfunction had ST segment depression during ambulatory monitoring. Moreover, patients with left ventricular dysfunction at rest had a lower prevalence of transient episodes of ST segment depression (31%) than did patients with normal left ventricular function at rest (62%) (p = 0.008). The relation between prognostically important variables during exercise radionuclide ventriculography and the number and duration of transient episodes of ST depression was examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term variation in the frequency of myocardial ischemia during daily activity in patients with coronary artery disease who do not experience symptomatic changes has not been documented. Because at one point in time, the magnitude of such ischemia is strongly related to the ischemic threshold measured during exercise testing, this study was undertaken to determine whether patients with stable coronary artery disease show long-term variations in the frequency and duration of myocardial ischemia and to establish whether such variability is related to parallel changes in the ischemic threshold during exercise testing.Forty consecutive patients (mean age 61 ± 8 years) who showed a stable clinical course over ≥12 months were studied with a repeat exercise treadmill test and ambulatory electrocardiographic (ECG) monitoring after withdrawal of antianginal medications. The ischemic threshold was determined as the exercise time at 1 mm of ST segment depression. The mean interval to both follow-up evaluations was 15 ± 3 months. Among the 23 patients with myocardial ischemia on ambulatory ECG monitoring at initial evaluation, the number and duration of ischemic episodes at follow-up were increased in 5 patients (mean increase 3.6 ± 2 episodes and 123 ± 98 min), unchanged in 1 patient and decreased in 17 patients (mean decrease 2.6 ± 2 episodes and 98 ± 72 min). Of the 17 patients without ischemic episodes at initial evaluation, 3 had evidence of ischemia on follow-up ambulatory ECG monitoring.During follow-up exercise testing, the exercise ischemic threshold decreased significantly (from 12.5 ± 6 to 8 ± 4 min; p < 0.001) in those patients in whom the frequency (and duration) of myocardial ischemia on ambulatory monitoring increased. Conversely, the ischemic threshold significantly increased (from 8 ± 5 to 10.2 ± 5 min; p < 0.001) in those patients in whom the number (and duration) of ischemic episodes decreased during follow-up. The variations in the frequency of myocardial ischemia during follow-up ambulatory monitoring significantly correlated with the changes in exercise ischemic threshold (r = −0.62; p < 0.0001).These findings indicate that patients with coronary artery disease may show long-term variations in myocardial ischemia during daily activity, even without simultaneous symptomatic changes. The occurrence and magnitude of this variation are closely related to parallel changes in the exercise ischemic threshold. These findings may have important implications for the understanding of the mechanisms and prevalence of ischemia during daily activity and the longitudinal evaluation of patients with stable coronary artery disease.

Background Platelets, long believed to be incapable of de novo protein synthesis, may retain their ability to form the cyclooxygenase (COX) enzyme once it has been inactivated by aspirin. This may explain the inefficacy of the drug to induce sustained platelet inhibition in certain patients. We evaluated the stability of platelet inhibition following once-daily enteric-coated aspirin administration. Methods Platelet responsiveness to aspirin was evaluated in 11 stable coronary artery disease patients on chronic aspirin therapy before and 1, 3, 8, and 24h after observed ingestion of 80-mg enteric-coated aspirin. Inhibition of the COX pathway was measured pharmacologically through plasma thromboxane (Tx) B 2 levels, and functionally by light transmission aggregometry in response to arachidonic acid. COX-independent platelet activity was measured in response to adenosine diphosphate, epinephrine and collagen. Results Plasma TxB 2 levels showed profound inhibition of TxA 2 formation, which was stable throughout 24h, in all but 1 subject. This subject had optimal response to aspirin (inhibition of platelet TxA 2 production within 1h), but recovered the ability to synthesize TxA 2 within 24h of aspirin ingestion. Arachidonic acid-induced platelet aggregation closely mirrored TxB 2 formation in this patient, portraying a functional ability of the platelet to aggregate within 24h of aspirin ingestion. COX-independent platelet aggregation triggered TxA 2 production to a similar extent in all patients, likely through signal-dependent protein synthesis. Conclusions COX-dependent platelet activity is recovered in certain individuals within 24h of aspirin administration. Further research should consider increasing aspirin dosing frequency to twice daily, to allow sustained inhibition in such subjects.

This study sought to assess whether inadequate platelet responses to aspirin and clopidogrel are distinct phenomena caused by different mechanisms or different facets of the same phenomenon (i.e., general platelet hyperactivity). A total of 85 patients with stable coronary artery disease who were taking aspirin and clopidogrel daily foror =3 months were enrolled in the present study. Platelet aggregation was measured by light transmission aggregometry (LTA) stimulated with 1.6 mM of arachidonic acid and 5, 10 and 20 microM of adenosine diphosphate, and by the VerifyNow Aspirin and VerifyNow P2Y12 point-of-care assays. An inadequate platelet response was defined as aggregation greater than or equal to the mean + 2 SDs. The prevalence of an inadequate platelet response varied greatly among the assays. For aspirin, the prevalence was 2.4% using arachidonic acid-induced LTA and 5.9% using the VerifyNow Aspirin assay. For clopidogrel, the prevalence varied from 1.2% to 3.9% using adenosine diphosphate-induced LTA and was 2.4% using the VerifyNow P2Y12 assay. The point-of-care assays did not select the same patients as LTA. No subject was unresponsive to both aspirin and clopidogrel, regardless of the assay used, suggesting that separate mechanisms govern platelet unresponsiveness to aspirin and clopidogrel. In conclusion, an inadequate platelet response to either aspirin or clopidogrel is rare, and the definition is dependent on the platelet function assay used. Because no subject was found to be unresponsive to both agents, the unresponsiveness is suspected to occur through distinct mechanisms of platelet activation.

Introduction When studying the efficacy of clopidogrel to inhibit platelet aggregation by light transmission aggregometry, technical decisions must be taken prior to assessment or during analysis, including, but not limited to, concentration of agonist to use and timing of the evaluation of the response on the aggregation curve obtained (peak ADP-stimulated platelet aggregation vs. late aggregation). We investigated how some of these technical modalities affected the results of platelet aggregation obtained after clopidogrel administration. Materials and methods One hundred and twenty stable coronary artery disease patients requiring a diagnostic angiography were recruited prior to pre-treatment with clopidogrel. Blood samples were tested before clopidogrel initiation and immediately preceding coronary angiography using light transmission aggregometry with either 5 or 20 µM of ADP. Aggregation was measured at maximal amplitude (peak), and 5 minutes after agonist addition (late). Results While measurements of platelet aggregation as either peak or late aggregation were strongly correlated, peak platelet aggregation was significantly higher than late aggregation, by 10.8% and by 10.3% with ADP 5 and 20 µM, respectively. Moreover, the use of ADP 20 µM resulted in less spontaneous disaggregation than 5 µM in the absence of clopidogrel (11.8% and 4.8% with ADP 5 µM and 20 µM, respectively). Conclusions When assessing platelet aggregation following clopidogrel, measurement of late aggregation after addition of ADP 20 µM should be preferred. Large clinical trials should be conducted to assess which parameter between residual aggregation or inhibition of platelet aggregation by clopidogrel best predicts clinical efficacy of the drug.

The relation between ambulatory myocardial ischemia and the results of exercise testing in patients with ischemic heart disease remains undefined, because of the dissimilar results of previous reports. To further investigate this issue and, in particular, to ascertain the importance of the exercise protocol in determining that relation, 70 patients with stable coronary artery disease underwent 48 h ambulatory electrocardiographic (ECG) monitoring and treadmill exercise tests after withdrawal of medications.Patients exercised using two different protocols with slow (National Institutes of Health [NIH] combined protocol) and brisk (Bruce protocol) work load increments. Exercise duration was longer with the NIH combined protocol (14.1 ± 5 versus 6.8 ± 2 min; p < 0.0001), but the maximal work load and peak heart rate achieved were greater with the Bruce protocol (9.8 ± 2 versus 6.5 ± 2 METs, and 142 ± 19 versus 133 ± 22 beats/min, respectively; p < 0.0001). A close inverse correlation between exercise testing and the results of ambulatory ECG monitoring was observed using the NIH combined protocol; the strongest correlation was observed between time of exercise at 1 mm of ST segment depression and number of ischemic episodes (r = −0.86; p < 0.0001). With the Bruce protocol a significantly weaker inverse correlation was found (r = −0.35). The mean heart rate at the onset of ST segment depression was similar during monitoring and during exercise testing with the NIH combined protocol (97.2 ± 13 versus 101.0 ± 17 beats/min, respectively) but it was significantly higher (110.4 ± 13) when using the Bruce protocol (p > 0.001).These findings indicate that a relation does exist between ambulatory myocardial ischemia and the results of the exercise test but this relation is critically determined by the exercise protocol and is better observed with protocols that produce slow work load increments. These observations raise questions about the independent value and usefulness of ambulatory ECG monitoring in patients with stable ischemic heart disease.

Aims We investigated the comparability of platelet function tests in quantifying platelet inhibition achieved by clopidogrel. Methods and results This pre-specified substudy of a randomized, double-blind trial included 116 patients with stable coronary artery disease requiring diagnostic angiography. Patients received clopidogrel for 1 (300 or 600 mg) or 7 days (300 + 75 or 150 mg daily) before the procedure. Blood samples obtained before clopidogrel initiation and before diagnostic coronary angiography were assayed using light transmission aggregometry [adenosine diphosphate (ADP) 5 and 20 microM as the agonist], whole-blood aggregometry (ADP 5 and 20 microM), PFA-100 (Collagen-ADP cartridge), and VerifyNow P2Y12. Although all assays studied were found sensitive to clopidogrel ingestion, none could distinguish categorically between patients who had, or not, ingested clopidogrel. Agreement between assays to identify patients with insufficient inhibition of platelet aggregation by clopidogrel was low. Conclusion The assessment of platelet function inhibition by clopidogrel is highly test-specific. Decision to increase clopidogrel dosage may vary on the basis of the assay used, thus highlighting the need for unambiguous guidelines with respect to assay selection, as platelet function assays are not interchangeable. At present, platelet function testing evaluating clopidogrel efficacy cannot be recommended in routine clinical practice.

The hemodynamic and platelet effects of prostacyclin (PGI2) were investigated in 27 patients with unstable angina (14 treated patients; 13 control subjects) given a 72-hour infusion (5 ng/kg/min) or placebo. This randomized study was double-blind and conducted as a substudy of a multicenter trial testing the clinical efficacy of PGI2. The clinical and angiographic features were identical in the 2 groups. Blood pressure and heart rate were not modified significantly by PGI2. A recurrence of angina during infusion occurred in 8 treated patients (57.1%) and in 8 control subjects (61.5%). Two patients receiving PGI2 and none in the control group developed a myocardial infarction. Levels of 6-keto-prostaglandin F1 alpha, a stable metabolite of PGI2, increased from baseline values (less than 20 pg/ml) to 605 +/- 41 pg/ml during infusion. Levels of fibrinopeptide A, beta-thromboglobulin, platelet factor 4, thromboxane B2 and the platelet aggregates ratio in blood were similar between the 2 groups before, during and after PGI2 infusion. Prostacyclin reduced ex vivo platelet aggregation to adenosine diphosphate and thromboxane B2 generation by approximately 50% during the infusion period with return of aggregation to baseline and platelet thromboxane B2 production to above baseline after the discontinuation of PGI2. Thus, despite favorable effects of PGI2 upon platelet aggregation and systemic hemodynamics, the prostanoid failed to improve the clinical evolution of unstable angina.

Background There have been few prospective studies examining the utility of routine exercise treadmill testing (ETT) early after percutaneous coronary intervention (PCI). The objective of this study was to examine the impact of a routine ETT strategy early after PCI on follow-up cardiac events and procedures. Methods We examined 136 patients who underwent routine ETT at 6 weeks post-PCI in the ADORE trial. The ETT was classified as positive, indeterminate, or negative. The Duke Treadmill Score (DTS) was calculated for all patients. Follow-up occurred at 9 months. Results ETT results at 6 weeks were: 32 (23.5%) positive, 24 (17.6%) indeterminate and 80 (58.8%) negative. At 9 months, the composite event rate was 21.9% in those with a positive ETT, 20.8% in those with an indeterminate ETT and 12.5% in those with a negative ETT (p = 0.25 positive vs. negative ETT). The sensitivity of early ETT for predicting clinical events was 41.2%, the specificity was 73.3%, the positive predictive value was 21.9% and the negative predictive value was 87.5%. At 9 months, the cardiac procedure rate was 18.8% in those with a positive test, 13.0% in those with an indeterminate test, and 6.3% in those with a negative test (p = 0.07 positive vs. negative ETT). In a multivariate logistic regression model, coronary stenting during PCI and a ≥ 85% MPHR achieved were found to be inversely associated with clinical events. However, the DTS did not independently predict clinical events. Conclusion Although the statistical power of the study was limited by the small number of clinical events (particularly MI and death), the results of this study support the ACC/AHA guidelines that exercise treadmill testing should not be used routinely after PCI.

BACKGROUND We investigated whether higher doses of ticlopidine combined with acetylsalicylic acid would allow a faster inhibition of platelet activation and aggregation in patients with acute coronary syndromes potentially undergoing percutaneous coronary intervention with stent placement. METHODS Seventeen patients presenting with acute coronary syndromes and candidates for possible percutaneous coronary intervention were randomized to ticlopidine 250 mg or 500 mg twice daily for 5 days. Platelet aggregation and activation were assessed at baseline before the first dose and daily for 5 days. RESULTS After 2 days of treatment, 500 mg twice daily of ticlopidine produced a significantly larger reduction in platelet activation and aggregation than 250 mg twice daily. Mean platelet activation was 17.6 +/- 3.3% lower with 500 mg twice daily from days 3 to 6 (P < or = 0.05). Mean platelet aggregation was 16.9 +/- 0.6% lower in patients treated with the higher dose on days 3 through 6 when compared with those on ticlopidine 250 mg twice daily (P < 0.05). CONCLUSIONS A faster and stronger inhibition of platelet activation and aggregation is obtained when 500 mg twice daily of ticlopidine is administered daily in combination with acetylsalicylic acid in patients with acute coronary syndromes.

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 μg/min) in 30 patients, 19 of whom had angiographic atherosclerosis. Measurements were repeated with sodium nitroprusside (40 μg/min), l -arginine (160 μmol/min), and N G -monomethyl- l -arginine (L-NMMA; 16 μmol/min). There was significant inhibition of collagen-induced platelet aggregation with ACh (45±9.5% lower, P 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 P 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.

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 μg/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.

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%; p0.01), 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)

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-life3 min) and the spermine/NO complex (SPER/NO) (half-life30 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.

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 or 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 ≥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 ≥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 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.

The platelet aggregation response to adenosine diphosphate (ADP) and to thrombin was quantified in 10 patients, 5 with unstable angina pectoris and 5 with acute myocardial infarction, before, during and after a 45-minute infusion of nitroglycerin. An impedance aggregometer allowing rapid bedside studies in whole blood was used. The reproducibility of the methods was documented to be within 10%. Doses of nitroglycerin were titrated for a 10 mm Hg decrease in mean arterial blood pressure with mean doses being 1.2 +/- 0.2 (standard error of the mean) micrograms/kg/min. Nitroglycerin decreased the area under the aggregation curve induced by ADP from 43 +/- 3.6 to 30 +/- 6.3 cm2 (p = 0.007) and by thrombin from 8.9 +/- 1.7 to 4.1 +/- 0.9 cm2 (p = 0.003). Peak responses to ADP were decreased from 13.3 +/- 1 to 9.1 +/- 1.7 ohms (p = 0.005) and to thrombin from 9.3 +/- 2 to 5.0 +/- 1.2 ohms (p = 0.003). All patients had greater than or equal to 50% inhibition with 1 agent or the other and the inhibition was greater than 50% with each of the 2 aggregating agents in 6 patients. Analyses performed on blood withdrawn 15 minutes after the discontinuation of nitroglycerin showed a return to baseline before nitroglycerin results. When analyses were delayed and performed on blood preserved at room temperature for 30 minutes, no effect of nitroglycerin could be detected. Thus, bedside platelet aggregation studies document a significant and reversible effect of nitroglycerin at therapeutic doses on platelet function.

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 nd 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.