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28. Haaf P, Drexler B, Reichlin T, et al. High-sensitivity cardiac troponin in the distinction of acute myocardial infarction from acute cardiac noncoronary artery disease. Circulation. 2012;126(1):31-40. 29. Haaf P, Reichlin T, Twerenbold R, et al. Risk stratification in patients with acute chest pain using three high-sensitivity cardiac troponin assays [published online July 14, 2013]. Eur Heart J. doi:10.1093/eurheartj/eht218. 30. Wildi K, Reichlin T, Twerenbold R, et al. Serial changes in high-sensitivity cardiac troponin I in the early diagnosis of acute myocardial infarction [published online July 30, 2013]. Int J Cardiol. doi:10.1016/j.ijcard.2013.07.078. 31. Meune C, Balmelli C, Twerenbold R, et al. Utility of 14 novel biomarkers in patients with acute chest pain and undetectable levels of conventional cardiac troponin. Int J Cardiol. 2013;167(4):11641169. 32. Shry EA, Dacus J, Van De Graaff E, Hjelkrem M, Stajduhar KC, Steinhubl SR. Usefulness of the response to sublingual nitroglycerin as a predictor of ischemic chest pain in the emergency department. Am J Cardiol. 2002;90(11):1264-1266. 33. Woodforde JM, Merskey H. Some relationships between subjective measures of pain. J Psychosom Res. 1972;16(3):173-178. 34. Reichlin T, Hochholzer W, Stelzig C, et al. Incremental value of copeptin for rapid rule out of acute myocardial infarction. J Am Coll Cardiol. 2009;54(1):60-68.

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35. Reiter M, Twerenbold R, Reichlin T, et al. Early diagnosis of acute myocardial infarction in the elderly using more sensitive cardiac troponin assays. Eur Heart J. 2011;32(11):1379-1389. 36. Kuster TM, Schleppi P, Hu B, Schulin R, Günthardt-Goerg MS. Nitrogen dynamics in oak model ecosystems subjected to air warming and drought on two different soils. Plant Biol (Stuttg). 2013;15(suppl 1):220-229. 37. Hahne H, Sobotzki N, Nyberg T, et al. Proteome wide purification and identification of O-GlcNAc–modified proteins using click chemistry and mass spectrometry. J Proteome Res. 2013;12(2):927-936. 38. Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. J Am Coll Cardiol. 2007;50(22):2173-2195.

41. Apple FS, Jesse RL, Newby LK, Wu AH, Christenson RH; National Academy of Clinical Biochemistry; IFCC Committee for Standardization of Markers of Cardiac Damage. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: analytical issues for biochemical markers of acute coronary syndromes. Circulation. 2007;115(13):e352-e355. doi:10.1161/circulationaha.107.182881. 42. Thygesen K, Mair J, Giannitsis E, et al; Study Group on Biomarkers in Cardiology of ESC Working Group on Acute Cardiac Care. How to use high-sensitivity cardiac troponins in acute cardiac care. Eur Heart J. 2012;33(18):2252-2257. 43. Goodacre SW, Angelini K, Arnold J, Revill S, Morris F. Clinical predictors of acute coronary syndromes in patients with undifferentiated chest pain. QJM. 2003;96(12):893-898.

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40. Thygesen K, Alpert JS, Jaffe AS, et al; Writing Group on the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction; ESC Committee for Practice Guidelines (CPG). Third universal definition of myocardial infarction. Eur Heart J. 2012;33(20):2551-2567.

45. Haasenritter J, Stanze D, Widera G, et al. Does the patient with chest pain have a coronary heart disease? diagnostic value of single symptoms and signs—a meta-analysis. Croat Med J. 2012;53(5):432-441.

Invited Commentary

Chest Pain in Acute Myocardial Infarction Are Men From Mars and Women From Venus? Louise Pilote, MD, MPH, PhD

In 1995, John Gray published a book entitled Men Are From Mars, Women Are From Venus.1 The premise of this book was that men and women have fundamental psychological differences that make them experience the world and reRelated article page 241 spond to situations in widely distinct ways. Could the same be true when it comes to chest pain in acute myocardial infarction (AMI)? Dissention remains in the medical literature, in the minds of the clinicians, and in the public at large as to whether men and women have fundamentally different presentations of AMI. Several studies have shown that the most common symptom at presentation in men and women is chest pain.2 Reports vary in the proportion of patients who present without chest pain, but the prevalence of presentation without chest pain is higher in women. More information on chest pain– associated symptoms and symptoms accompanying presentation without chest pain might prove useful in improving the diagnosis of AMI in women. With the above premises in mind, Rubini Gimenez et al asked whether detection of sex-specific chest pain characterjamainternalmedicine.com

istics (CPCs) would allow emergency department physicians to diagnose AMI in women more accurately.3 The authors conducted a large prospective cohort study in 7 European centers (5 Swiss, 1 Italian, and 1 Spanish) to investigate the predictive value of CPCs. From 2006 to 2012, the investigators assembled a cohort of 2475 patients, 796 women and 1679 men, who presented to an emergency department within 12 hours of the onset of acute chest pain. The median age of men was more than 10 years younger that of women (59 vs 70 years), and a higher proportion of men had had a previous AMI (28.2% vs 15.1%) and revascularization (32.9% vs 17.3%). Thirty-four predefined CPCs were collected with regard to the location and size of the area of pain, pain quality, radiation, onset, duration, dynamics, severity, and the aggravating and relieving factors (eg, response to nitrates). Chest pain characteristics were collected in the emergency department through interviews by trained physicians who were blinded to the electrocardiography and cardiac troponin test results. All patients underwent electrocardiography and chest radiography; levels of cardiac troponin at presentation and serially thereafter were measured if clinically indicated. All medical records were reviewed twice for adjudication of the final diagnosis by 2 independent reviewers. JAMA Internal Medicine February 2014 Volume 174, Number 2

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Research Original Investigation

Sex-Specific Chest Pain Characteristics in AMI

The study revealed that none of the CPCs were more useful at enhancing the posttest probability of AMI in women compared with men. Although women and men reported 9 CPCs with different frequency, none of these CPCs were helpful in differentiating women with AMI from women with other causes of chest pain. Even if the CPCs related to pain duration and dynamics had a better likelihood ratio in women than men, these likelihood ratios still were close to 1. Finally, only 18.0% of women and 22.0% of men presenting with chest pain received a diagnosis of AMI. The authors are to be congratulated for providing clarification on whether men and women have fundamental differences in their presentation of chest pain. Their work clarifies that presentation of chest pain between men and women is not as different as is commonly thought and provides new knowledge on the value and limitation of chest pain in making a diagnosis of AMI in women as well as in men. As with all studies, the present study has several limitations. First, the generalizability of the findings is dampened by the fact that the study population is drawn from a limited number of European centers. Second, the women were 10 years older than the men, and this difference was not considered in the interpretation of the results. With advanced age, presentations without chest pain become increasingly common, and differences between men and women decrease with age. Age has previously been found to be a stronger determinant of different symptoms at AMI presentation than sex.4 Third, a greater proportion of men than women had experienced a previous AMI, and these patients may have been more aware of their symptoms. Fourth, an evaluation of whether high-sensitivity cardiac troponin testing provides an additive value to CPCs in distinguishing the cause of chest pain may be useful. Finally, the authors stated a second objective to test the hypothesis that physicians’ diagnostic uncertainty was more common in women with acute chest pain than in men; however, these reARTICLE INFORMATION Author Affiliations: McGill University Health Center Research Institute, Montréal, Quebec, Canada; Division of General Internal Medicine, McGill University Health Center, Montréal, Quebec, Canada; Division of Clinical Epidemiology, McGill University Health Center, Montréal, Quebec, Canada. Corresponding Author: Louise Pilote, MD, MPH, PhD, McGill University Health Center Research Institute, 687 Pine Ave W, V Building, Montreal, QC H3A 1A1, Canada. Published Online: November 25, 2013. doi:10.1001/jamainternmed.2013.12097.

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sults were not reported. Physicians’ estimation of risk has been found to be an essential element in diagnostic reasoning. A low estimation of risk in women is likely to lessen the chance that additional diagnostic testing will be performed. We might speculate how the message conveyed by this article will be received by the public. A recently published study5 investigated sex differences in symptoms at acute coronary syndrome presentation in adults 55 years or younger. The main finding was that for more than 80% of patients, the predominant symptom is chest pain. The main difference at presentation was that women were more likely than men to present without chest pain (19.0% vs 13.7%). Patients without chest pain reported fewer symptoms overall, and no discernible pattern of non–chest pain symptoms was found that could help the physician identify acute coronary syndrome in women without chest pain. The focus of the media, however, stressed the differences in non–chest pain presentation rather than the highly prevalent similar chest pain presentation in both sexes. The identification of sex-specific symptoms remains a challenge. Is the premise of Men Are From Mars, Women Are From Venus a useful model for chest pain in AMI? Emerging data, including those from the study by Rubini Gimenez et al, increasingly suggest that it is not. Although modest differences occur between men and women in their presentations of AMI, overall they are similar. In addition, although modest numbers of patients present without chest pain, any combination of their presentation symptoms is not frequent enough to be diagnostic. Instead, clinicians will have to maintain a high level of clinical suspicion and increasingly use sensitive biomarkers, such as high-sensitivity cardiac troponin tests, to help diagnose AMI in high-risk women. Rather than the model of Men Are From Mars, Women Are From Venus, George Carlin may have had it right when he said: “Men are from earth, women are from earth—deal with it!” (http://www.goodreads.com/author /quotes/22782.George_Carlin).

Conflict of Interest Disclosures: None reported.

online November 25, 2013]. JAMA Intern Med. doi:10.1001/jamainternmed.2013.12199.

REFERENCES

4. Canto JG, Rogers WJ, Goldberg RJ, et al; NRMI Investigators. Association of age and sex with myocardial infarction symptom presentation and in-hospital mortality. JAMA. 2012;307(8):813-822.

1. Gray J. Men Are From Mars, Women Are From Venus: A Practical Guide for Improving Communication and Getting What You Want in Your Relationships. New York, NY: HarperCollins; 1992. 2. Canto JG, Goldberg RJ, Hand MM, et al. Symptom presentation of women with acute coronary syndromes: myth vs reality. Arch Intern Med. 2007;167(22):2405-2413. 3. Rubini Gimenez M, Reiter M, Twerenbold R, et al. Sex-specific chest pain characteristics in the early diagnosis of acute myocardial infarction [published

5. Khan NA, Daskalopoulou SS, Karp I, et al; GENESIS PRAXY Team. Sex differences in acute coronary syndrome symptom presentation in young patients [published online September 16, 2013]. JAMA Intern Med. doi:10.1001 /jamainternmed.2013.10149.

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Chest pain in acute myocardial infarction: are men from Mars and women from Venus?

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