Evidence of platelet sensitization to ADP following discontinuation of clopidogrel therapy in patients with stable coronary artery disease.

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.

Genetic determinants of response to aspirin: appraisal of 4 candidate genes.

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 Pl(A1/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.

Heterogeneity in platelet cyclooxygenase inhibition by aspirin in 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.

Comparison of electrocardiographic recordings in open-chest and closed-chest swine models.

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.

Platelet count, not oxidative stress, may contribute to inadequate platelet inhibition by aspirin.

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>or=20% per arachidonic acid-induced light transmission aggregometry. Morning urinary samples were used to determine levels of isoprostanes (8-iso-PGF2alpha) 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-PGF2alpha 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-PGF2alpha 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.

Complementary prognostic values of ST segment deviation and Thrombolysis In Myocardial Infarction (TIMI) risk score in non-ST elevation acute coronary syndromes: Insights from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study.

BACKGROUND: Although the Thrombolysis In Myocardial Infarction (TIMI) score incorporates ST deviation, it does not account for characteristics of the ST deviations. In the present study, it was hypothesized that the magnitude and characteristics of ST deviation may add to the prognostic values of the TIMI risk score in acute coronary syndrome (ACS) patients, particularly in lower-risk patients with a TIMI risk score of less than 5. OBJECTIVE: To evaluate the prognostic value of combining the TIMI risk score and characteristics of ST deviation in patients with non-ST elevation ACS and a TIMI risk score of less than 5. METHODS: The death/myocardial infarction (MI) rates of 1296 patients enrolled in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) angiographic substudy were examined. RESULTS: Patients without a TIMI risk score of 5 or greater, and without an ST deviation of 1 mm or greater had the lowest six-month rate of death/ MI (5%). In patients with a TIMI risk score of less than 5, the six-month death/MI rate was increased in those with ST depression of 2 mm or greater compared with patients with a similar TIMI risk score and without ST deviation of 1 mm or greater (24% versus 5%, P<0.001). The presence of ST deviation of 2 mm or greater identified an additional 15% of patients with an increased six-month death/MI rate in patients with a TIMI risk score of less than 5. CONCLUSION: ST segment deviation of 2 mm or greater confers additional prognostic information in non-ST elevation ACS patients with a TIMI risk score of less than 5. Patients with a TIMI risk score of less than 5 and ST deviation of 2 mm or less had the lowest risk of six-month death/MI.

Prevalence of unresponsiveness to aspirin and/or clopidogrel in patients with stable coronary heart disease.

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 for > or =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.

Week-long high-maintenance dose clopidogrel regimen achieves better platelet aggregation inhibition than a standard loading dose before percutaneous coronary intervention: results of a double-blind, randomized clinical trial.

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 microM 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.

Response to aspirin in healthy individuals. Cross-comparison of light transmission aggregometry, VerifyNow system, platelet count drop, thromboelastography (TEG) and urinary 11-dehydrothromboxane B(2).

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.

Possibility of a rebound phenomenon following antiplatelet therapy withdrawal: a look at the clinical and pharmacological evidence.

The importance of regular administration of antiplatelet drugs in patients suffering from coronary artery disease stands on firm grounds, as large meta-analyses have shown these therapies to drastically reduce the risk of death. Although the current guidelines published jointly by the American Heart Association, the American College of Cardiology, the Society for Cardiovascular Angiography and Interventions, the American College of Surgeons and the American Dental Association stress the hazards of premature discontinuation of antiplatelet drugs, abrupt withdrawal remains widespread, with potentially catastrophic consequences. In the limited state of knowledge on antiplatelet drug withdrawal, an early sound of alarm has risen from early thromboembolic complications reported after the interruption of treatment in patients who require antiplatelet therapy for prevention of ischemic vascular disease. Acute thrombotic complications are not immediate and usually follow interruption of aspirin or clopidogrel therapy after a mean delay of 8-25 days, a time lapse consistent with normal platelet turnover required to replace the platelet pool in circulation and suggestive of a rebound phenomenon. This review article describes the thrombotic risks associated with discontinuing antiplatelet therapy and the bleeding risks associated with continuing these drugs. By integrating the current understanding of the pharmacology of antiplatelet agents and the kinetics of platelet function recovery, this article unveils the possibility of a pharmacological rebound phenomenon which could lead to adverse ischemic events, and supports the warning against premature discontinuation of antiplatelet drugs issued in current guidelines.

Insights into the interpretation of light transmission aggregometry for evaluation of platelet aggregation inhibition by clopidogrel.

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 microM 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 microM, respectively. Moreover, the use of ADP 20 microM resulted in less spontaneous disaggregation than 5 microM in the absence of clopidogrel (11.8% and 4.8% with ADP 5 microM and 20 microM, respectively). CONCLUSIONS: When assessing platelet aggregation following clopidogrel, measurement of late aggregation after addition of ADP 20 microM 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.

Evaluation of the platelet count drop method for assessment of platelet function in comparison with "gold standard" light transmission aggregometry.

INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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, p<0.0001 for ADP 5 microM and r=0.402, p<0001 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. CONCLUSIONS: 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.

Comparison of four tests to assess inhibition of platelet function by clopidogrel in stable coronary artery disease patients.

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.

Assessment of VerifyNow P2Y12 assay accuracy in evaluating clopidogrel-induced platelet 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.

A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease.

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 (> or =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 microM) stimulation, (iii) whole blood aggregometry, (iv) PFA-100, (v) VerifyNow Aspirin; urinary 11-dehydro-thromboxane B(2) 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 B(2) 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.

Aspirin resistance: truth or dare.

Acetylsalicylic acid, or aspirin (ASA), is widely used in patients with cardiovascular disease to prevent acute ischemic events. However, platelet response to ASA is not equal in all individuals, and a high variability in the prevalence of ASA resistance is reported in the literature (0.4-83%). Actually, ASA resistance is poorly understood; this stems from the fact that its definition is unclear, its presence can be evaluated by a number of assays that are not equivalent, and its prevalence may vary widely based on the population studied. This article (1) exposes the difficulties in defining ASA resistance; (2) discusses the mechanisms by which ASA resistance may occur; (3) presents the characteristics that may put patients at greater risk of exhibiting ASA resistance; and (4) discusses the clinical impact of ASA resistance in patients requiring chronic therapy.

Progressive epicardial coronary blood flow reduction fails to produce ST-segment depression at normal heart rates.

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.

Absence of clinically significant increase in pulmonary artery pressure after intravenous perflutren injection for myocardial perfusion imaging in pigs.

OBJECTIVE: 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. METHODS: Five anesthetized, ventilated, open-chest pigs were administered perflutren intravenously at a rate of 0.0364 mL/kg/min over approximately 5 minutes. RESULTS: 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. CONCLUSION: 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.