Peter A. McCullough M.D.

Vasudevan, A., A. J. Singer, C. DeFilippi, G. Headden, J. M. Schussler, L. B. Daniels, M. Reed, M. P. Than, R. Birkhahn, S. W. Smith, T. W. Barrett, W. Arnold, W. F. Peacock and P. A. McCullough (2017). “Renal function and scaled troponin in patients presenting to the emergency department with symptoms of myocardial infarction.” Am J Nephrol 45(4): 304-309.

Full text of this article.

BACKGROUND: Cardiac troponins are often found to be elevated in patients with renal dysfunction, even in the absence of acute myocardial injury. The objective of this report was to characterize the scaled troponin values and proportion of adjudicated acute myocardial infarction (AMI) among patients with and without renal dysfunction. METHODS: The data was from a multicenter prospective study including patients presenting to the emergency department with symptoms of AMI. Troponin measurements were standardized across various assays by calculating the observed results as multiples of the assay-specific 99th percentile upper limit of normal. Patients with an estimated glomerular filtration rate (eGFR; calculated by the Chronic Kidney Disease Epidemiology Collaboration formula) <60 mL/min/1.73 m2 were considered to have renal dysfunction. RESULTS: Of 430 included patients, 249 (58%) were male and 181 (42%) were female, with a mean age of 55.9 +/- 12.3 and 57.3 +/- 12.8 years, respectively. Eighty-seven (20.2%) had renal dysfunction. The proportions of patients with at least one scaled troponin value above the 99th percentile cut-off point among patients with and without renal dysfunction were 40 (45.9%) and 81 (23.6%) respectively (p < 0.001). The proportions of patients with an adjudicated diagnosis of AMI among those with and without renal dysfunction were 20.7 and 18.7%, respectively (p = 0.67). Using scaled troponins, by the second test there was >5X and by the third test >15X separation in the excursion of troponin among those with AMI compared to those without. CONCLUSIONS: One or more elevated troponin values are common in those with renal dysfunction. Scaled troponins for eGFR groups were similar, indicating that the use of this interpretative technique is applicable in discerning AMI for those with and without renal dysfunction.

McCullough, P. A., A. Vasudevan, M. Sathyamoorthy, J. M. Schussler, C. E. Velasco, L. R. Lopez, C. Swift, M. Peterson, J. Bennett-Firmin, R. Schiffmann and T. Bottiglieri (2017). “Urinary 11-dehydro-thromboxane b2 and mortality in patients with stable coronary artery disease.” Am J Cardiol: 2017 Jan [Epub ahead of print].

Full text of this article.

Antiplatelet therapy with aspirin has been shown to reduce adverse outcomes in patients with coronary artery disease (CAD). Aspirin irreversibly inhibits platelet cyclooxygenase-1 and attenuates thromboxane A2 (TXA2)-mediated platelet aggregation, but there is variable suppression of cyclooxygenase-1. From a cohort of patients with stable CAD, we performed blinded, detailed chart abstraction, and measured urinary 11-dehydro-thromboxane B2 (11dhTxB2), an inactive metabolite of TxA2 from frozen samples. There were 327 men (73%) and 122 women (27%) with a mean age (+/-SD) of 67 +/- 10 and 65 +/- 10 years, respectively. A positive linear trend for age was observed among tertiles of 11dhTxB2 (p trend = 0.01). Higher proportions of women (p = 0.001), chronic obstructive pulmonary disease (p trend = 0.0003), and heart failure (p trend = 0.003) were observed in the upper tertile of 11dhTxB2. Sixty-seven patients (14.9%) died over a median follow-up of 1,149 days and 87.5% of the deaths were due to cardiovascular causes. Twenty-six nonsurvivors (38.8%) were treated with P2Y12 receptor antagonists versus 161 survivors (42.2%; p = 0.61). By stepwise Cox proportional hazards analysis, we identified that patients in the middle (hazard ratio 7.14; 95% CI 2.46 to 20.68) and upper tertiles (hazard ratio 9.91; 95% CI 3.45 to 28.50) had higher risks for mortality after adjusting for age and co-morbidities. In conclusion, urinary concentration of 11dhTxB2 was a strong independent risk factor for all-cause mortality among patients with stable CAD on aspirin therapy and may be a marker for patients with CAD who require more intensive secondary prevention measures.

Singer, A. J., M. P. Than, S. Smith, P. McCullough, T. W. Barrett, R. Birkhahn, M. Reed, H. C. Thode, W. D. Arnold, L. B. Daniels, C. de Filippi, G. Headden and W. F. Peacock (2017). “Missed myocardial infarctions in ed patients prospectively categorized as low risk by established risk scores.” Am J Emerg Med: 2017 Jan [Epub ahead of print].

Full text of this article.

STUDY OBJECTIVES: Few studies have prospectively compared multiple cardiac risk prediction scores. We compared the rate of missed acute myocardial infarction (AMI) in chest pain patients prospectively categorized as low risk by unstructured clinical impression, and by HEART, TIMI, GRACE, and EDACS scores, in combination with two negative contemporary cardiac troponins (cTn) available in the U.S. METHODS: We enrolled 434 patients with chest pain presenting to one of seven emergency departments (ED). Risk scores were prospectively calculated and included the first two cTn. Low risk was defined for each score as HEART

McCullough, P. A., A. Vasudevan, L. R. Lopez, C. Swift, M. Peterson, J. Bennett-Firmin, R. Schiffmann and T. Bottiglieri (2016). “Oxidative stress reflected by increased F2-isoprostanes is associated with increasing urinary 11-dehydro thromboxane B2 levels in patients with coronary artery disease.” Thromb Res 148: 85-88.

Full text of this article.

Our study demonstrated that: 1) CAD patients with higher levels of 8-isoPGF2α had higher levels of 11dhTxB2, which could be related to poor inhibition of COX-1 pathway in spite of adequate ASA treatment, 2) 8-isoPGF2α is an independent determinant of 11dhTxB2 and 3) 8-isoPGF2α levels were significantly higher in females and patients with diabetes and COPD. Patients with diabetes and central obesity have been observed to have an incomplete ASA response manifested as incomplete inhibition of thromboxane production, in a pro-inflammatory background with enhanced oxidative stress. Oxidative stress enhances the production of platelet isoprostanes and is believed to mitigate the aspirin mediated TxA2 inhibition among diabetic patients on low-dose aspirin [9]. Among F2-isoprostanes metabolites, 8-isoPGF2α is a marker of in vivo oxidative stress, which has been shown to stimulate the activation of platelets by direct binding to the thromboxane platelet receptor. Elevated 8-isoPGF2α levels in our ASA-treated CAD patients indicate the presence of an active oxidative stress environment that is not affected by ASA treatment. Because ASA inhibits over 95% of platelet COX-1 activity in practically all subjects, the residual platelet activation in poor ASA responders can be explained by alternative sources of TxA2 produced by non-platelet inflammatory COX-2 pathways. Our findings are congruent with the notion that oxidative stress mechanisms play an important role in platelet activation in addition to their role on the initiation, progression, and consequences of atherogenesis. Excessive production of ROS may damage lipoproteins creating an inflammatory and atherogenic background and also enhance the arachidonic acid production of F2-isoprostanes that are capable of activating platelets and making them resistant to the therapeutic effect of ASA. These observations support the concept that oxidative stress maintains platelet hyperactivity linking proatherogenic mechanisms to platelet dysfunction in patients with stable CAD. Considering that thromboxanes are not the only factor contributing to platelet activation and atherothrombosis, it is not surprising that a single anti-platelet agent such as ASA does not prevent all adverse events. Cyclo-oxygenase-1 derived TxA2 activates the same and nearby platelets in an autocrine signaling fashion. Due to the very short half-life of TxA2 (20–30 s) and low concentrations (1–60 pg/mL), a constant production of TxA2 is necessary to maintain a homeostatic (physiologic) control of platelet activity. However, the half-life of 8-isoPGF2α is much longer (10 min), with concentrations that are thirty-fold higher. If 8-isoPGF2α can bind and stimulate thromboxane platelet receptors with similar affinity, its longer half-life and concentration makes it a relevant agonist for platelet activation in patients with an underlying oxidative process. Because ASA blocks most of COX-1 activity reducing the production of TxA2, it is possible that the thromboxane platelet receptor can still be activated by TxA2 produced via the 8-isoPGF2α pathway. In this situation, blocking 8-isoPGF2α TPR stimulation could be a potential therapeutic target instead of increasing the dose of ASA. Sex related differences in platelet function and ASA pharmacokinetics exist with female gender associated with elevated 11dhTxB2. We found that females had significantly higher 8-isoPGF2α levels, suggesting an enhanced oxidative stress and lesser attenuation of TxA2. Elevated 11dhTxB2 was found to increase the risk of adverse events in patients with stable CAD and myocardial infarction. (Excerpt from text, p. 86-87.)

Vasudevan, A., T. Bottiglieri, K. M. Tecson, M. Sathyamoorthy, J. M. Schussler, C. E. Velasco, L. R. Lopez, C. Swift, M. Peterson, J. Bennett-Firmin, R. Schiffmann and P. A. McCullough (2016). “Residual thromboxane activity and oxidative stress: Influence on mortality in patients with stable coronary artery disease.” Coron Artery Dis: 2016 Dec [Epub ahead of print].

Full text of this article.

BACKGROUND: Aspirin use is effective in the prevention of cardiovascular disease; however, not all patients are equally responsive to aspirin. Oxidative stress reflected by F2-isoprostane [8-iso-prostaglandin-F2alpha (8-IsoPGF2alpha)] is a potential mechanism of failure of aspirin to adequately inhibit cyclooxygenase-1. The objective was to examine the relation between all-cause mortality and the concentrations of urinary 11-dehydro thromboxane B2 (11dhTxB2) and 8-IsoPGF2alpha in patients with stable coronary artery disease (CAD). METHODS: The data for this analysis are from a prospective study in which patients were categorized into four groups based on the median values of 11dhTxB2 and 8-IsoPGF2alpha. RESULTS: There were 447 patients included in this analysis with a median (range) age of 66 (37-91) years. The median (range) values of 11dhTxB2 and 8-IsoPGF2alpha were 1404.1 (344.2-68296.1) and 1477.9 (356.7-19256.3), respectively. A total of 67 (14.9%) patients died over a median follow-up of 1149 days. The reference group for the Cox proportional hazards survival analysis was patients with values of 11dhTxB2 and 8-IsoPGF2alpha below their corresponding medians. Adjusting for the age and sex, patients with values of 11dhTxB2 greater than the median had a significantly higher risk of mortality when compared with the reference group (high 11dhTxB2 and low 8-IsoPGF2alphaadj: hazard ratio: 3.2, 95% confidence interval: 1.6-6.6, P=0.002; high 11dhTxB2 and 8-IsoPGF2alphaadj: hazard ratio: 3.6, 95% confidence interval: 1.8-7.3, P<0.001). The findings were similar when we adjusted for the comorbidities of cancer, kidney function, and ejection fraction. CONCLUSION: We found that 11dhTxB2 appears to be a better prognostic marker for mortality as compared with 8-IsoPGF2alpha, suggesting aspirin resistance itself is a stronger independent determinant of death in CAD patients treated with aspirin.