Non-Traditional ACS Risk Factors: A Snake in the Grass

Authors: Adrianna Long, MD (@EMDrLong ‏, EM Attending Physician, US Army) and Brit Long, MD (@long_brit , EM Attending Physician, SAUSHEC, USAF)// Edited by: Alex Koyfman, MD (@EMHighAK – EM Attending Physician, UT Southwestern Medical Center / Parkland Memorial Hospital) and Manpreet Singh, MD (@MPrizzleER – Assistant Professor of Emergency Medicine / Department of Emergency Medicine – Harbor-UCLA Medical Center)

Case

A 32-year-old female presents with chest pain, which she describes as central chest in location with radiation to both shoulders that began while going up the stairs in her apartment complex.  She has had several episodes of nausea, but she denies vomiting, diaphoresis, dyspnea, or pain in any other location. She also denies recent travel, lower extremity swelling, and neurologic symptoms.

Her vital signs include HR 82, BP 143/77, T 37C, RR 18, and Sat 98% RA. Her exam is normal, with clear lungs and normal cardiac exam. Pulses are equal bilaterally, and she has no extremity swelling, redness, or edema.

You ask for an ECG, and one of your technicians hands you this:

Really? A STEMI in a 32-year-old? You quickly go back into the room and order aspirin and fentanyl, while activating the STEMI team.  The patient states she has lupus and is on methotrexate, and in the past she has required several courses of corticosteroids.

Non-Traditional ACS Risk Factors

As emergency physicians, we manage patients with Acute Coronary Syndrome (ACS) on a daily basis. The medical community has come to universally recognize the so-called “classic” ACS risk factors, including age, hypertension, hyperlipidemia, diabetes, obesity, smoking history, and family history (first degree relatives). As laid out in a prior post (http://www.emdocs.net/missed-myocardial-infarction-in-the-emergency-department/), these traditional risk factors are effective for population use, but not for the patient in front of you in the ED. Close to 12% of patients will not demonstrate classic risk factors with acute myocardial infarction (MI).^1,2 Awareness of the risk factors attributable to coronary heart disease (CHD), appropriate preventive measures, and initial treatments for Acute Myocardial Infarction (AMI) and Unstable Angina (UA) have shown to decline the CHD mortality rates in the United States. In 2013, the total deaths associated with underlying CHD in the Untied States was approximately 1 out of every 7, which is decreased from approximately 1 out of every 3.^3,4

What other patient populations are at risk for developing atherosclerotic disease and ACS that emergency physicians can miss? If our community is responsible for recognizing and treating initial presentations of patients with ACS, we must not only be aware of atypical presentations of ACS, but also non-traditional risk factors for CHD.

1.) Chronic Kidney Disease (CKD)

While there is controversy whether CKD is an independent cause of cardiovascular disease (CVD), there is a clear relationship between patients who have CKD and incidence of CVD events. Individuals who have CKD are more likely to die from CVD events rather than progress to end-stage renal disease (ESRD).³ There are multiple risk factors for CKD including autoimmune disease, systemic infection, drug exposure, urinary tract infections, urinary stones, urinary tract obstruction, and neoplasm; however, even when adjusting for these risk factors, there is an excessive risk for CVD.⁵ Furthermore, CKD has a higher associated risk with recurrent CHD events than diabetes, cigarette smoking, and metabolic syndrome.⁶

2.) Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA)

When examining what would normally be a younger and healthier population with no other risk factors, autoimmune disorders are a predisposing factor to the development of CVD events. A systemic review of 28 studies examining the epidemiology of cardiovascular disease in patients with SLE found that patients with SLE have at least double the risk of having CVD as compared to the general population.⁷  Similarly, a meta-analysis of 24 studies concluded that patients with RA have a 59% higher risk of CVD mortality.⁸ It is believed that the chronic inflammation may accelerate the progression of atherosclerosis in both of these diseases, yet the mechanism is not yet known.

Additionally, patients with autoimmune diseases and severe symptoms are more likely to be placed on corticosteroids. Corticosteroids can exacerbate hyperlipidemia, diabetes, and obesity, as well as atherosclerosis.⁹

3.) Human Immunodeficiency Virus (HIV)

Studies have indicated that patients with HIV have a 1.5-fold increased risk of cardiovascular events, particularly in patients over 45 years old.^10,11 Antiretroviral therapy (ART) has significantly decreased the deaths associated with infection in patients with HIV, but these medications may lead to metabolic changes that further increase chances of cardiovascular events in this patient population. Patients are ART medications have changes in fat distribution, increased chances of dyslipidemia, diabetes mellitus, hypertension, and coagulation abnormalities, amongst other side effects.¹²

4.) History of Cancer

The type of cancer and prior treatments affect risk of CVD. Survivors of Hodgkin Lymphoma have been shown to have a higher risk of death from myocardial infarction. This may be related to supradiaphragmatic radiation therapy, as well as treatment with anthracycline or vincristine.¹³ Several studies have estimated the increased risk of fatal cardiovascular events in Hodgkin lymphoma survivors to range from 2.2 to 7.6-fold greater than the general population.^13-15

Cancer patients undergoing treatment with chemotherapy are at higher risk for cardiovascular complications, especially if they have a history of heart disease. Patients with HER2 positive breast cancer undergoing treatment with trastuzumab or other HER2-targeted agents have as high as a 27% risk of cardiotoxicity and subsequent cardiac events.¹⁶

Serious cardiac-associated complications that have been reported with chemotherapy include:

• Arrhythmias (histone deacetylase inhibitors, nilotinib, ponatinib, vandetanib, crizotinib, vemurafenib, taxanes)
• Myocardial necrosis causing a dilated cardiomyopathy and heart failure (sunitinib, alemtuzumab, imatinib [in patients treated for chronic myelogenous leukemia], trametinib, taxanes [in combination with anthracyclines])
• Vasospasm or vaso occlusion resulting in chest pain or myocardial infarction (fluoropyrimidines).
• Pericarditis (cytarabine, bleomycin)
• Pericardial effusions (all-trans retinoic acid)
• Heart failure, myocardial ischemia, and cardiac arrest (proteasome inhibitors, antiangiogenic therapies, interferon, interleukin-2 [IL-2])
• Fluid retention, which may be manifest as a pericardial or pleural effusion (bosutinib, IL-2)¹⁷

5.) Heavy Alcohol Consumption

While many studies have indicated that moderate alcohol consumption is associated with a reduction in cardiovascular mortality, heavy alcohol consumption has been shown to increase mortality. A prospective study over 8 years showed that men who consumed greater than 6 alcoholic drinks per day were at higher risk for sudden cardiac death.¹⁸ Another prospective study over 12 years showed an increase mortality in men with a history of CHD who drank three or more drinks per day.¹⁹ Additionally, binge drinking has been shown to increase the risk of cardiovascular disease. One study indicates that the risk for MI or coronary death is doubled in binge drinkers as compared to non-drinkers.²⁰

6.) Pregnancy

While MI is rare in reproductive-age women, pregnancy is thought to triple or quadruple this risk. The incidence of MI in pregnant patients was higher with maternal age >30, smoking or cocaine use, untreated hypertension, thrombophilia, multiparity, after transfusions, and those with post-partum infections.^21,22

7.) Systemic Infection

Acute infection, including pneumonia, influenza, and sepsis, are also risk factors for MI and progression of CVD.^23-28 Infection can induce ischemia, increased inflammation leading to atherosclerotic plaques, endothelial dysfunction, and pro-coagulant changes in the patient’s blood. One study of patients hospitalized with pneumonia found that there is a significantly higher risk of patients having CVD within one year after hospitalization (14.7% with pneumonia had CVD events, as compared to the controls in this study with 5.9% CVD events in the same timeframe). ²⁹ Another study also found that patients admitted to the hospital have a higher risk of acute cardiovascular events within 90 days after admission with sepsis, with sources of infection including pneumonia and urinary tract infections.³⁰ Two studies recommended consideration of antiplatelet therapy in these patients as a preventive measure upon admission to the hospital.^30,31

Key Points

• Traditional risk factors are for population use only, not for the patient in front of you in the ED with a great story.
• Several significant non-traditional risk factors are associated with ACS.
• Patients with CKD are at high risk for ACS, as it is the most common cause of death in this population.
• Vasculitis predisposes to atherosclerosis and ACS development, as does the use of corticosteroids.
• HIV and antiretroviral therapies predispose to ACS.
• Specific types of cancer, radiation therapy, and chemotherapy are significant risk factors.
• Heavy alcohol use increases risk of sudden cardiac death.
• Pregnancy is associated with 3-4X the risk of MI.
• Systemic infections such as pneumonia and sepsis are associated with increased mortality in ACS.

References/Further Reading

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3. Writing Group M, Mozaffarian D, Benjamin EJ, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016;133(4):e38-360.
4. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics–2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117(4):e25-146.
5. Coresh J, Astor B, Sarnak MJ. Evidence for increased cardiovascular disease risk in patients with chronic kidney disease. Curr Opin Nephrol Hypertens. 2004;13(1):73-81.
6. Baber U, Gutierrez OM, Levitan EB, et al. Risk for recurrent coronary heart disease and all-cause mortality among individuals with chronic kidney disease compared with diabetes mellitus, metabolic syndrome, and cigarette smokers. Am Heart J. 2013;166(2):373-380 e372.
7. Schoenfeld SR, Kasturi S, Costenbader KH. The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: a systematic review. Semin Arthritis Rheum. 2013;43(1):77-95.
8. Avina-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum. 2008;59(12):1690-1697.
9. Petri M, Lakatta C, Magder L, Goldman D. Effect of prednisone and hydroxychloroquine on coronary artery disease risk factors in systemic lupus erythematosus: a longitudinal data analysis. Am J Med. 1994;96(3):254-259.
10. Currier JS, Taylor A, Boyd F, et al. Coronary heart disease in HIV-infected individuals. J Acquir Immune Defic Syndr. 2003;33(4):506-512.
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20. Ruidavets JB, Ducimetiere P, Evans A, et al. Patterns of alcohol consumption and ischaemic heart disease in culturally divergent countries: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). BMJ. 2010;341:c6077.
21. Ladner HE, Danielsen B, Gilbert WM. Acute myocardial infarction in pregnancy and the puerperium: a population-based study. Obstet Gynecol. 2005;105(3):480-484.
22. James AH, Jamison MG, Biswas MS, Brancazio LR, Swamy GK, Myers ER. Acute myocardial infarction in pregnancy: a United States population-based study. Circulation. 2006;113(12):1564-1571.
23. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006;367(9524):1747-1757.
24. Warren-Gash C, Smeeth L, Hayward AC. Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review. Lancet Infect Dis. 2009;9(10):601-610.
25. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med. 2004;351(25):2611-2618.
26. Ramirez J, Aliberti S, Mirsaeidi M, et al. Acute myocardial infarction in hospitalized patients with community-acquired pneumonia. Clin Infect Dis. 2008;47(2):182-187.
27. Corrales-Medina VF, Madjid M, Musher DM. Role of acute infection in triggering acute coronary syndromes. Lancet Infect Dis. 2010;10(2):83-92.
28. Clayton TC, Thompson M, Meade TW. Recent respiratory infection and risk of cardiovascular disease: case-control study through a general practice database. Eur Heart J. 2008;29(1):96-103.
29. Corrales-Medina VF, Alvarez KN, Weissfeld LA, et al. Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease. JAMA. 2015;313(3):264-274.
30. de Groot B, van den Berg S, Kessler J, Ansems A, Rijpsma D. Independent predictors of major adverse cardiovascular events in emergency department patients who are hospitalised with a suspected infection: a retrospective cohort study. BMJ Open. 2016;6(1):e009598.
31. Falcone M, Russo A, Cangemi R, et al. Lower mortality rate in elderly patients with community-onset pneumonia on treatment with aspirin. J Am Heart Assoc. 2015;4(1):e001595.