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Coronary Artery Disease in Young Adults
REVIEW ARTICLE
Coronary Artery Disease in Young Adults Hassan Alkhawam, MD, Feras Zaiem, MD, Robert Sogomonian, MD, Mohammed El-Hunjul, MD, Mohamad Al-kateb, MD, M. Umair Bakhsh, MD and Raef Madanieh, MD
Abstract: Coronary heart disease (CHD) sustains a significant negative impact on hospital admissions and deaths worldwide. The prevalence of CHD in young adults is difficult to establish accurately, as these asymptomatic patients typically do not undergo diagnostic studies. In this article, the authors will focus on young adults with CHD emphasizing common and uncommon risk factors, current management and review of previous studies. Key Indexing Terms: Coronary artery disease; Acute coronary syndrome; Young adults. [Am J Med Sci 2015;350(6):479–483.]
studied in an autopsy study of 760 (aged 15–34 years) victims of accidents, suicides or homicides.5 Advanced coronary atheroma in 2% of men was identified and none in women, aged 15 to 19 years. An advanced lesion was present in 20% and 8% of men and women aged 30 to 34 years, respectively. There is a male predominance as shown in 2 series of patients with coronary artery disease at #40 years of age; women consisted only of 5.6% and 11.4% of patients.6,7
ETIOLOGY AND PATHOPHYSIOLOGY
H
istorically, the development of coronary artery disease leading to coronary heart disease (CHD) is largely concentrated on middle-aged and elderly population. Overlooking the younger population remains a common practice given no early signs, symptoms and low lifetime risk predictors of CHD with Framingham’s score and other scoring system alike. However, by educating patients and ensuring that risk factors are well understood may help reduce CHD. Over time, CHD mortality has decreased in the past 30 years yet remains as the leading cause of deaths in adults worldwide.1 In 2004, 2,400 Americans died of cardiovascular disease each day at an average rate of 1 death every 37 seconds. Compared to 2006 update, 2,300 Americans died each day at a rate of 1 death every 38 seconds because of cardiovascular disease. A difference in 451,326 deaths compared to 425,425 in 1 year.2,3 Reduction in deaths each year may likely be achieved through education and risk factor modification. In this article, the authors will address coronary artery disease in young adults with significant risk factors to further address and aim to decrease cardiovascular disease as atherosclerotic maturity may begin at early stages of life.
PREVALENCE Although coronary artery disease seems to be more prevalent in patients older than 40 years, younger men and women may also be affected. Incidence of myocardial infarction and symptomatic coronary artery disease in young adults are low; studies indicate approximately 3% of all coronary artery disease cases occurring in patients younger than 40 years.4 However, the prevalence of coronary artery disease in younger subjects is difficult to establish and likely underestimated as asymptomatic young patients typically do not undergo medical investigations. The frequency of this occurrence was From the Department of Medicine (HA, RS), Elmhurst Hospital Center, Icahn School of Medicine at Mount Sinai, New York City, New York; Mayo Evidence Based Practice Center- Mayo Clinic (FZ), Rochester, Minnesota; Departments of Medicine (MEH), Presence Saint Joseph Hospital, Chicago, Illinois; Intervention Cardiology (MAK), Beth Israel Deaconess Medical Center, Boston, Minnesota; Department of Medicine (MUB), Mount Sinai St. Luke’s Hospital, New York City, New York; and Center for Advanced Cardiac Therapeutics (RM), Saint Francis Hospital- The Heart Center, Roslyn, NY. Submitted July 9, 2015; accepted in revised form August 12, 2015. The authors have no financial or other conflicts of interest to disclose. Correspondence: Hassan Alkhawam, MD, Department of Medicine, Elmhurst Hospital Center, Icahn School of Medicine at Mount Sinai, 7901 Broadway, Elmhurst, NY 11373 (E-mail: [email protected]).
The American Journal of the Medical Sciences
The main precipitant of coronary artery disease is atherosclerosis. Athermanous inflammatory process seems similar to the process of aging, intimal thickening, fatty streaks, calcified nodule and plaque development.8 The process of atherosclerosis begins developing early in life as shown in a study of a group of young adults (ages between 30 and 34 years old) who died of different causes, 20% of men and 8% of women demonstrated advanced CHD.5 Another study of 262 subjects demonstrated early development of atherosclerosis, which approximately 16% of teenagers had atherosclerotic disease.9 Unlike the elderly, studies that evaluated risk factors of developing coronary artery disease in young adults are limited. Generally, the conventional risk factors for coronary artery disease in elderly are typically present in younger population as well.10 Smoking is the primary risk factor for developing coronary artery disease. A total of 71% of patients younger than 35 years who underwent diagnostic coronary angiography had a history of smoking.11 In another study, 77% of patients younger than 35 years who presented with acute coronary syndrome were current smokers.12 Various studies have shown that juvenile-onset insulin-dependent diabetes mellitus, hypercholesterolemia, elevated triglyceride levels and low high-density lipoprotein levels were associated with coronary artery disease in young adults.13–15 Finally, obesity had a strong association with atherosclerosis and subclinical CHD.16 Various nonatherosclerotic factors may also be associated with coronary artery disease in young adults; a study indicated that approximately 20% diagnosed with myocardial infarction have a nonatherosclerotic etiology.17 Cocaine use is associated with atherosclerosis as it induces coronary vasoconstriction and promotes thrombosis.18–22 For every 4 myocardial infarctions, 1 case had frequent use of cocaine in patients aged from 18 to 45 years.23 Furthermore, acute ethanol intoxication and elevated homocysteine levels are established risk factors.24,25 In addition, increase in hostility measured in (CARDIA) study may increase coronary calcification.26 Connective tissue diseases such as Kawasaki disease is a well-known cause of CHD in children.27 Hypercoagulable pathologies may induce coronary artery disease such as antiphospholipid syndrome causing thrombotic occlusion in the coronary artery, resulting in myocardial infarction.28 In nephrotic syndrome, excretion of anticoagulant factors together with dyslipidemia creates a hypercoagulable environment.29 Similarly, factor V Leiden mutation valuable in maintaining a balanced coagulable state may also precipitate coronary artery disease.30 Family history is important as genetic factors such as
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diabetes, coagulopathies and lipoproteins disorders lead to coronary artery disease.
STUDIES Young patients with myocardial infarctions typically have multiple risk factors for developing coronary artery disease. Importance of risk factors for development of coronary artery disease according to age was evaluated in a report in which 11,016 men aged from 18 to 39 years were followed for 20 years. The relative risks associated with traditional risk factors were similar in a group of 8,955 men aged from 40 to 59 years. These included; age (relative risk of 1.63 per 6-year increase), serum cholesterol (relative risk 1.92 per 40 mg/dL increase), systolic blood pressure (relative risk of 1.32 per 20 mm Hg increase) and cigarette smoking (relative risk is 1.36 per 10 cigarette/day increases).31 Another study was performed to assess risk factors, extent and severity of coronary artery disease in 200 patients aged 35 years or younger who underwent diagnostic coronary angiography.11 Smoking (71%) and history of premature coronary artery disease (27%) were the 2 most frequent risk factors. History of previous ST elevation myocardial infarction (STEMI) was present in 68% of patients. Majority (54.5%) was treated conservatively and the rest (45.5%) required either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). Smoking was the main risk factor in the previous study and it has also been supported by another report, where smoking is noted in 65% to 92% of young patients with myocardial infarction compared with 24% to 56% of patients older than 45 years.7 Younger patients with coronary artery disease more often have a family history of premature coronary artery disease. A higher incidence of positive family history in young patients (64%) was illustrated in the largest report of 823 patients.3 Obesity seems to be an independent risk factor for coronary atherosclerosis in young men. This was observed in a report from the Framingham Heart Study that suggests obesity in middle-aged patients may account for as much as 23% of cases with coronary artery disease in men and 15% in women.32 A recent published review in 2014 indicated that acute myocardial infarction in young patients almost exclusively occurs in males, with STEMI being the main diagnosis.33 Anterior wall myocardial infarction is the most common, with left anterior descending artery involvement in approximately two thirds of patients. The study included 124 patients diagnosed with myocardial infarction younger than 40 years with coronary angiography performed in all. Of 124 patients, 123 were men (mean age of 36). A total of 118 patients had STEMI (95%) and 6 with non-ST elevation myocardial infarction (NSTEMI) (6%). Anterior wall myocardial infarction was present in 88 patients (71%), inferior wall myocardial infarction in 31 (25%) and lateral wall myocardial infarction in 5 (4%). Significant coronary artery disease was found in 88 patients (71%) and 13 (10%) had normal coronaries. Single-vessel disease was observed in 57 patients (46%), 2-vessel disease in 15 (12%) and 3-vessel disease in 8 (6%). A total of 125 lesions were identified with left anterior descending artery which is the most common vessel involved with a total of 78 lesions (62%).34 Coronary artery disease in young adults carries a poor long-term prognosis as shown in a report, where 843 patients younger than 40 years diagnosed with coronary artery disease were identified and followed for 15 years.6 The strongest predictors of long-term mortality were; previous myocardial infarction (hazard ratio [HR] 1.32, 95% confidence interval [CI]
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1.00–1.73), New York Heart Association class II heart failure (HR 1.75, 95% CI 1.03–2.97) and active tobacco use (HR 1.59, 95% CI 1.14–2.21). Revascularization, rather than medical management, was associated with lower mortality (coronary angioplasty: HR 0.51, 95% CI 0.32–0.81; CABG: HR 0.68, 95% CI 0.50–0.94). However, overall mortality was 30% at 15 years. Patients with diabetes had 15-year mortality of 65%. Those with previous myocardial infarction had 15-year mortality of 45% and patients with an ejection fraction ,30% had 15-year mortality of 83%.34 In a prospective study, of over 7,000 women with a mean age of 27 years were followed for an average of 31 years, resulting in 47 coronary artery disease deaths.35 Coronary artery disease mortality rates for those with no risk factors, only 1 risk factor or 2 or more risk factors were 0.7, 2.4 and 5.4 per 1,000 person-years, respectively. A comparable relationship was observed for cardiovascular disease mortality and for allcause mortality.35
MANAGEMENT Acute Management Initial management of myocardial infarction in younger patients differs slightly from management in adults. Initial management with oxygen, morphine, nitrates and aspirin should be administered in all patients. In patients with positive history of cocaine use, beta-blockers must be delayed for 48 hours as it may result in severe coronary spasm and paradoxical worsening of chest pain. Benzodiazipines are recommended as the standard management of myocardial infarction in cocaine users, along with nitrates to counteract coronary spasm.36 Patients with cocaine-induced persistent ST elevation not resolved with nitrates should be offered thrombolytic therapy. In patients with persistent ST-segment elevation after nitrate and benzodiazepines, the 2007 ACC/AHA Task Force guidelines recommend the immediate coronary angiography and PCI, if indicated.37 Fibrinolytic therapy is an acceptable alternative only when timely coronary angiography is not possible.38 However, many patients with a history of cocaine use likely to be noncompliant for a long-term antiplatelet therapy. Therefore, the risk of stent thrombosis should be compared to the risk of conservative medical therapy and the choice should be made after pros and cons had been weighted. In addition, there is an increased rate of stent thrombosis with both bare metal stents and drug eluting stents (DESs) as reported in patients with cocaine-associated myocardial ischemia.39,40 So when a decision has been made to place a stent, bare metal stents should be chosen in preference to DESs.37 ST Elevation Myocardial Infarction Young patients with acute STEMI require revascularization either with primary PCI or, CABG if not available, thrombolytic therapy. The AHA recommends emergency CABG in the acute settings mainly (class I indication) in patients who failed PCI or when PCI cannot be performed; this is specifically recommended in those with suitable coronary anatomy and persistent ischemia or hemodynamic instability. CABG is also recommended in the acute setting when surgical intervention is indicated because of either acute papillary muscle dysfunction causing mitral regurgitation or in the case of myocardial rupture.41 Prospective randomized trials assessing primary PCI versus thrombolytic therapy for acute STEMI observed that both young and old patients have better outcomes with PCI compared with thrombolysis. However, younger patients have Volume 350, Number 6, December 2015
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superior outcomes compared with elderly, regardless of the therapy received. Irrespective of treatment, risk increases with age, after adjusting for baseline characteristics, as each increment of 10 years of age increased the risk of death or reinfarction by 1.32 times. Although data are limited, young patients also seem to respond well to thrombolytic therapy.42,43 In a study, clinical responses to streptokinase, as measured by TIMI II or III flow in an infarcted artery, were similar in patients younger than 35 and older than 55 years (74% versus 73%).42 Non-ST Elevation Myocardial Infarction Patients with a NSTEMI, NSTEMI or unstable angina are initially stabilized with medical therapy and should undergo early coronary angiography and revascularization, if appropriate. Higher risk patients should be referred to specialists to assess for early coronary angiography and intervention, if needed. Coronary angiography is not routinely offered in younger patients as significant numbers of patients tend to have normal coronary arteries. The efficacy of this approach is illustrated by the following study. One report evaluated 129 patients younger than 40 years, who had coronary angiography within 60 days of their 1st acute myocardial infarction.44 Patients without evidence of spontaneous or induced ischemia were compared to those who had ischemia or abnormal stress test after myocardial infarction. Conclusion was to offer early coronary angiography only for young patients with multiple risk factors or recurrent ischemia. Many other low-risk patients with uncomplicated course may undergo exercise stress testing as it is a simpler and more cost-effective modality for risk stratification before discharge. Echocardiographic assessment of left ventricular function is recommended in all patients.45 Chronic Management Management of stable angina, including indications for revascularization, is similar in both younger and older patients. Routine coronary angiography is not recommended in young patients who have stable coronary artery disease. However when indicated, both PCI and CABG are effective with lower risks in younger patients compared with elderly. Long-term outcome for young patients undergoing PCI is good.46,47 Success rates with percutaneous procedures were high in younger patients (93%). Ten-year overall and event-free survival without myocardial infarction, repeat PCI or elective CABG after PCI were 96% and 58%, respectively. Currently, DESs and glycoprotein IIb-IIIa inhibitors have success rates, which are expected to be higher with long-term studies pending.48 CABG is better performed in young patients as they are commonly in healthier physical condition compared with elderly and can better tolerate surgical stress with general anesthesia. CABG should be offered to patients with triplevessel disease, impaired left ventricular function and complex coronary artery abnormalities. Patients younger than 40 years were shown to have survival rates of 92% at 5 years and 86% in 10 years compared to 75% and 58% in patients older than 65 years.49 Arterial grafts are generally preferred to venous grafts because of longevity in patency as a study showed a survival rate of 91%, 74% and 50% at 5, 10 and 15 years, respectively, in patients younger than 40 years.50 In the nonacute setting and with multi-vessel disease, complete revascularization using bilateral internal mammary arteries (T-graft performed in 85% of patients) was shown to have less mortality compared with conventional CABG when Copyright © 2015 by the Southern Society for Clinical Investigation.
performed electively. To note, the study population age was younger than 70 years.51
PREVENTION Primary Prevention Despite little evidence addressing coronary artery disease prevention in young adults, decreasing modifiable risk factors remains the hallmark of reducing and preventing the disease. Lifestyle modification is significant in management of coronary artery disease and smoking cessation is strongly recommended. Extensive progression of CHD was noted in younger patients who continued to smoke after bypass surgery.43 Exercise and weight loss is recommended by American Heart Association as they were shown to increase high-density lipoprotein and decrease triglyceride levels. In addition, physical activity has been shown to improve endothelial function.52 Diabetes Control and Complications Trial indicated that patients with strict glycemic control in type 1 diabetes had less atherosclerosis, assessed by measuring carotid intima-media thickness.53 Control of diabetes and dyslipidemia was shown to have better prognosis in patients younger than 45 years. Risk factor modification may perhaps prove to be a challenging yet life-altering task in young population.54 Secondary Prevention Coronary artery disease in young patients carries a better prognosis, if appropriately managed. Poor risk factor control carries a significantly high morbidity and mortality.53 Medication management with antiplatelet agents such as aspirin and clopidogrel is essential. In addition, warfarin use is important in patients with coagulopathies and recurrent thrombotic events.48 Patients with suspicion for coronary spasm, beta-blocker administration must be delayed to prevent worsening of coronary vasoconstriction. Statins are invariably prescribed in patients with coronary artery disease as clinical benefits extend beyond lipid-lowering capabilities. Statins improve outcome and reduce recurrent events. Other agents such as niacin and omega 3 fatty acids should be considered in special circumstances as in low high-density lipoprotein levels and hypertriglyceridemia.55,56 Finally, angiotensin-converting enzyme inhibitors should be offered to all patients with left ventricular dysfunction as it has been approved in reducing mortality in this group of patients.57,58
CONCLUSIONS Cardiovascular disease is a leading health and economic burden as it is one of the leading causes of morbidity and mortality in middle-to-elderly aged population. Due to lack of symptoms in younger population, prevalence of coronary artery disease and CHD is yet to be accurately established. Different modifiable risk factors exist, such as smoking, obesity and dyslipidemia, which are strongly associated with the development of coronary artery disease. In younger adults, smoking is the most modifiable risk factor. Early detection, counseling and modifying risk factors are important in decreasing coronary artery disease and long-term complications in young adults. Moreover, awareness of uncommon risk factors such as coagulopathies and connective tissue disorders is essential in young adults. REFERENCES 1. Lloyd-Jones DM, Larson MG, Beiser A, et al. Lifetime risk of developing coronary heart disease. Lancet 1999;353:89.
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2. 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: e25–e146.
23. Qureshi AI, Suri MF, Guterman LR, et al. Cocaine use and the likelihood of nonfatal myocardial infarction and stroke: data from the Third National Health and Nutrition Examination survey. Circulation 2001;103:502–506.
3. Lloyd-Jones D, Adams RJ, Brown TM, et al. Executive summary: heart disease and stroke statistics–2010 update: a report from the American Heart Association. Circulation 2010;121:948.
24. Williams MJ, Restieaux NJ, Low CJ. Myocardial infarction in young patients with normal coronary arteries. Heart 1998;79:191–4.
4. Jalowiel DA, Hill JA. Myocardial infarction in the young and in women. Cardiovasc Clin 1989;20:197–206.
25. Foody JM, Milberg JA, Robinson K, et al. Homocysteine and lipoprotein (a) interact to increase CAD risk in young men and women. Arteriosclerosis Thromb Vasc Biol 2000;20:493–9.
5. McGill HC Jr, McMahan CA, Zieske AW, et al. Association of Coronary Heart Disease Risk Factors with microscopic qualities of coronary atherosclerosis in youth. Circulation 2000;102:374.
26. Iribarren C, Sidney S, Bild DE. Association of hostility with coronary artery calcification in young adults. the CARDIA study. Coronary Artery Risk Development in Young Adults. JAMA 2000;283:2546–51.
6. Fournier JA, Sánchez A, Quero J, et al. Myocardial infarction in men aged 40 years or less: a prospective clinical-angiographic study. Clin Cardiol 1996;19:631.
27. Takahashi K, Oharaseki T, Yokouchi Y. Pathogenesis of Kawasaki disease. Clin Exp Immunol 2011;164(suppl 1):20–2.
7. Cole JH, Miller JI III, Sperling LS, et al. Long-term follow-up of coronary artery disease presenting in young adults. J Am Coll Cardiol 2003;41:521.
28. Jouhikainen T, Pohjola-Sintonen S, Stephansson E. Lupus anticoagulant and cardiac manifestation in systemic lupus erythematosus. Lupus 1994;3:167.
8. Stary HC. Atlas of atherosclerosis: progression and regression. 2nd ed. New York (NY): Parthenon publishing Group; 2003.
29. Osula S, Bell GM, Hornung RS. Acute myocardial infarction in young adults: causes and management. Postgrad Med J 2002;78:27–31.
9. Tuzcu EM, Kapadia SR, Tutar E, et al. High prevalence of coronary atherosclerosis in asymptomatic teenagers and young adults: evidence from intravascular ultrasound. Circulation 2001;103:2705–10.
30. Tanis BC, Bloemankamp DG, Van Den Bosch MA, et al. Prothrombotic coagulation defects and cardiovascular risk factors in young women with acute myocardial infarction. Br J Haematol 2003;1:471.
10. Chan MY, Woo KS, Wong HB, et al. Antecedent risk factors and their control in young patients with a first myocardial infarction. Singapore Med J 2006;47:27–30.
31. Navas-Nacher EL, Colangelo L, Beam C, et al. Risk factors for coronary heart disease in men 18 to 39 years of age. Ann Intern Med 2001;134:433.
11. Christus T, Shukkur AM, Rashdan I, et al. Coronary artery disease in patients aged 35 or less—a different beast? Heart Views 2011;12:7–11.
32. Wilson PW, D’Agostino RB, Sullivan L, et al. Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch Intern Med 2002;162:1867.
12. Schoenenberger AW, Radovanovic D, Stauffer JC, et al. Acute coronary syndromes in young patients: presentation, treatment and outcome. Int J Cardiol 2011;148:300–4. 13. Krolewski AS, Kosinski EJ, Warram JH. Magnitude and determinants of coronary artery disease in juvenile onset, insulin dependent diabetes mellitus. Am J Cardiol 1987;59:750–5. 14. Klag MJ, Ford DE, Mead LA. Serum cholesterol in young men and subsequent cardiovascular disease. N Engl J Med 1993;328:313–18. 15. Isser HS, Puri VK, Narain VS, et al. Lipoprotein (a) and lipid levels in young patients with myocardial infarction and their first-degree relatives. Indian Heart J 2001;53:463–6. 16. Reis JP, Loria CM, Lewis CE, et al. Association between duration of overall and abdominal obesity beginning in young adulthood and coronary artery calcification in middle age. JAMA 2013;310:280–8. 17. Choudhury L, Marsh JD. Myocardial infarction in young patients. Am J Med 1999;107:254–61. 18. Patrizi R, Pasceri V, Sciahbasi A, et al. Evidence of cocaine-related coronary atherosclerosis in young patients with myocardial infarction. J Am Coll Cardiol 2006;47:2120–2122. 19. Dressler FA, Malekzadeh S, Roberts WC. Quantitative analysis of amounts of coronary arterial narrowing in cocaine addicts. Am J Cardiol 1990;65:303–308. 20. Flores ED, Lange RA, Cigarroa RG, et al. Effect of cocaine on coronary artery dimensions in atherosclerotic coronary artery disease: enhanced vasoconstriction at sites of significant stenoses. J Am Coll Cardiol 1990;16:74–79. 21. Heesch CM, Wilhelm CR, Ristich J, et al. Cocaine activates platelets and increases the formation of circulating platelet containing microaggregates in humans. Heart 2000;83:688–695. 22. Kugelmass AD, Oda A, Monahan K, et al. Activation of human platelets by cocaine. Circulation 1993;88:876–883.
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33. Bhardwaj R, Kandoria A, Sharma R. Myocardial infarction in young adults-risk factors and pattern of coronary artery involvement. Niger Med J 2014;55:44–7. 34. Cole JH, Miller J, Sperling LS, et al. Long-term follow-up of coronary disease presenting in young adults. J Am Coll Cardiol 2003; 41:521. 35. Daviglus ML, Stamler J, Pirzada A, et al. Favorable cardiovascular risk profile in young women and long-term risk of cardiovascular and all-cause mortality. JAMA 2004;292:1588. 36. Lange RA, Hills CD. Cardiovascular complications of cocaine use. N Engl J Med 2001;345:351–8. 37. McCord J, Jneid H, Hollander JE, et al. Management of cocaineassociated chest pain and myocardial infarction: a scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Circulation 2008;117:1897. 38. Hollander JE, Wilson LD, Leo PJ, et al. Complications from the use of thrombolytic agents in patients with cocaine associated chest pain. J Emerg Med 1996;14:731. 39. Lemos PA. Hidden drugs, hidden risks–is cocaine use a new risk factor for stent thrombosis? Catheter Cardiovasc Interv 2007;69:959. 40. McKee SA, Applegate RJ, Hoyle JR, et al. Cocaine use is associated with an increased risk of stent thrombosis after percutaneous coronary intervention. Am Heart J 2007;154:159. 41. David Hillis L, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: Executive summary a report of the american College of Cardiology Foundation/American heart association task force on practice guidelines. ACCF/AHA Practice Guideline J Am Coll Cardiol 2011. 42. Chouhan L, Hajar HA, Pomposiello JC. Comparison of thrombolytic therapy for acute myocardial infarction in patients aged , 35 and . 55 years. Am J Cardiol 1993;71:157.
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43. Moccetti T, Malacrida R, Pasotti E, et al. Epidemiologic variables and outcome of 1972 young patients with acute myocardial infarction. Data from the GISSI-2 database. Investigators of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI-2). Arch Intern Med 1997;157:865. 44. Negus BH, Willard JE, Glamann DB, et al. Coronary anatomy and prognosis of young, asymptomatic survivors of myocardial infarction. Am J Med 1994;96:354. 45. Klein LW, Agarwal JB, Herlich MB, et al. Prognosis of symptomatic coronary artery disease in young adults aged 40 years or less. Am J Cardiol 1987;60:1269–72. 46. Buffet P, Colasante B, Feldmann L, et al. Long-term follow-up after coronary angioplasty in patients younger than 40 years of age. Am Heart J 1994;127:509. 47. Mehan VK, Urban P, Dorsaz PA, et al. Coronary angioplasty in the young: procedural results and late outcome. J Invasive Cardiol 1994;6:202. 48. Mukherjee D, Hsu A, Moliterno DJ, et al. Risk factors for premature coronary artery disease and determinants of adverse outcomes after revascularisation in patients less than 40 years old. Am J Cardiol 2003;92:1465–7. 49. Floten HS, Ahmed A, Swanson JS, et al. Long term survival after post infarction bypass operation, early and late operation. Ann Thorac Surg 1989;48:757. 50. Ng WK, Vedder M, Whitlock RM, et al. Coronary revascularisation in young adults. Eur J Cardiothorac Surg 1997;11:732. 51. Wendler Olaf, Hennen Benno, Demertzis Stefanos, et al. Complete arterial revascularization in Multivessel coronary artery disease with 2
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Conduits (Skeletonized Grafts and T Grafts). Circulation 2000;102: 1179-83. 52. Woo KS, Chook P, Yu CW, et al. Effects of diet and exercise on obesity‐related vascular dysfunction in children. Circulation 2004;109: 1981–6. 53. Nathan DM, Lachin J, Cleary P, et al; For the Diabetes Control and Complications Trial, Epidemiology of Diabetes Interventions and Complications Research Group. Intensive diabetes therapy and carotid intima‐media thickness in type 1 diabetes mellitus. N Engl J Med 2003;348:2294–303. 54. Fox K; The EUROpean trial on reduction of cardiac events with perindopril in stable coronary artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised double blind, placebo controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782–8. 55. Schafer AI, Levine MN, Konkle BA, et al. Thrombotic disorders: diagnosis and treatment. Hematology Am Soc Hematol Educ Program 2003:520–39. 56. Miller M. Niacin as a component of combination therapy for dyslipidaemia. Mayo Clin Proc 2003;78:735–42. 57. Din JN, Newby DE, Flapan AD. Omega 3 fatty acids and cardiovascular disease—fishing for a natural treatment. BMJ 2004;328: 30–5. 58. The Heart Outcomes Prevention Evaluation study investigators. Effects of angiotensin converting enzyme inhibitor ramipril on cardiovascular events in high-risk patients. N Engl J Med 2000; 342:145.
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Coronary Artery Disease in Young Adults Hassan Alkhawam, MD, Feras Zaiem, MD, Robert Sogomonian, MD, Mohammed El-Hunjul, MD, Mohamad Al-kateb, MD, M. Umair Bakhsh, MD and Raef Madanieh, MD
Abstract: Coronary heart disease (CHD) sustains a significant negative impact on hospital admissions and deaths worldwide. The prevalence of CHD in young adults is difficult to establish accurately, as these asymptomatic patients typically do not undergo diagnostic studies. In this article, the authors will focus on young adults with CHD emphasizing common and uncommon risk factors, current management and review of previous studies. Key Indexing Terms: Coronary artery disease; Acute coronary syndrome; Young adults. [Am J Med Sci 2015;350(6):479–483.]
studied in an autopsy study of 760 (aged 15–34 years) victims of accidents, suicides or homicides.5 Advanced coronary atheroma in 2% of men was identified and none in women, aged 15 to 19 years. An advanced lesion was present in 20% and 8% of men and women aged 30 to 34 years, respectively. There is a male predominance as shown in 2 series of patients with coronary artery disease at #40 years of age; women consisted only of 5.6% and 11.4% of patients.6,7
ETIOLOGY AND PATHOPHYSIOLOGY
H
istorically, the development of coronary artery disease leading to coronary heart disease (CHD) is largely concentrated on middle-aged and elderly population. Overlooking the younger population remains a common practice given no early signs, symptoms and low lifetime risk predictors of CHD with Framingham’s score and other scoring system alike. However, by educating patients and ensuring that risk factors are well understood may help reduce CHD. Over time, CHD mortality has decreased in the past 30 years yet remains as the leading cause of deaths in adults worldwide.1 In 2004, 2,400 Americans died of cardiovascular disease each day at an average rate of 1 death every 37 seconds. Compared to 2006 update, 2,300 Americans died each day at a rate of 1 death every 38 seconds because of cardiovascular disease. A difference in 451,326 deaths compared to 425,425 in 1 year.2,3 Reduction in deaths each year may likely be achieved through education and risk factor modification. In this article, the authors will address coronary artery disease in young adults with significant risk factors to further address and aim to decrease cardiovascular disease as atherosclerotic maturity may begin at early stages of life.
PREVALENCE Although coronary artery disease seems to be more prevalent in patients older than 40 years, younger men and women may also be affected. Incidence of myocardial infarction and symptomatic coronary artery disease in young adults are low; studies indicate approximately 3% of all coronary artery disease cases occurring in patients younger than 40 years.4 However, the prevalence of coronary artery disease in younger subjects is difficult to establish and likely underestimated as asymptomatic young patients typically do not undergo medical investigations. The frequency of this occurrence was From the Department of Medicine (HA, RS), Elmhurst Hospital Center, Icahn School of Medicine at Mount Sinai, New York City, New York; Mayo Evidence Based Practice Center- Mayo Clinic (FZ), Rochester, Minnesota; Departments of Medicine (MEH), Presence Saint Joseph Hospital, Chicago, Illinois; Intervention Cardiology (MAK), Beth Israel Deaconess Medical Center, Boston, Minnesota; Department of Medicine (MUB), Mount Sinai St. Luke’s Hospital, New York City, New York; and Center for Advanced Cardiac Therapeutics (RM), Saint Francis Hospital- The Heart Center, Roslyn, NY. Submitted July 9, 2015; accepted in revised form August 12, 2015. The authors have no financial or other conflicts of interest to disclose. Correspondence: Hassan Alkhawam, MD, Department of Medicine, Elmhurst Hospital Center, Icahn School of Medicine at Mount Sinai, 7901 Broadway, Elmhurst, NY 11373 (E-mail: [email protected]).
The American Journal of the Medical Sciences
The main precipitant of coronary artery disease is atherosclerosis. Athermanous inflammatory process seems similar to the process of aging, intimal thickening, fatty streaks, calcified nodule and plaque development.8 The process of atherosclerosis begins developing early in life as shown in a study of a group of young adults (ages between 30 and 34 years old) who died of different causes, 20% of men and 8% of women demonstrated advanced CHD.5 Another study of 262 subjects demonstrated early development of atherosclerosis, which approximately 16% of teenagers had atherosclerotic disease.9 Unlike the elderly, studies that evaluated risk factors of developing coronary artery disease in young adults are limited. Generally, the conventional risk factors for coronary artery disease in elderly are typically present in younger population as well.10 Smoking is the primary risk factor for developing coronary artery disease. A total of 71% of patients younger than 35 years who underwent diagnostic coronary angiography had a history of smoking.11 In another study, 77% of patients younger than 35 years who presented with acute coronary syndrome were current smokers.12 Various studies have shown that juvenile-onset insulin-dependent diabetes mellitus, hypercholesterolemia, elevated triglyceride levels and low high-density lipoprotein levels were associated with coronary artery disease in young adults.13–15 Finally, obesity had a strong association with atherosclerosis and subclinical CHD.16 Various nonatherosclerotic factors may also be associated with coronary artery disease in young adults; a study indicated that approximately 20% diagnosed with myocardial infarction have a nonatherosclerotic etiology.17 Cocaine use is associated with atherosclerosis as it induces coronary vasoconstriction and promotes thrombosis.18–22 For every 4 myocardial infarctions, 1 case had frequent use of cocaine in patients aged from 18 to 45 years.23 Furthermore, acute ethanol intoxication and elevated homocysteine levels are established risk factors.24,25 In addition, increase in hostility measured in (CARDIA) study may increase coronary calcification.26 Connective tissue diseases such as Kawasaki disease is a well-known cause of CHD in children.27 Hypercoagulable pathologies may induce coronary artery disease such as antiphospholipid syndrome causing thrombotic occlusion in the coronary artery, resulting in myocardial infarction.28 In nephrotic syndrome, excretion of anticoagulant factors together with dyslipidemia creates a hypercoagulable environment.29 Similarly, factor V Leiden mutation valuable in maintaining a balanced coagulable state may also precipitate coronary artery disease.30 Family history is important as genetic factors such as
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diabetes, coagulopathies and lipoproteins disorders lead to coronary artery disease.
STUDIES Young patients with myocardial infarctions typically have multiple risk factors for developing coronary artery disease. Importance of risk factors for development of coronary artery disease according to age was evaluated in a report in which 11,016 men aged from 18 to 39 years were followed for 20 years. The relative risks associated with traditional risk factors were similar in a group of 8,955 men aged from 40 to 59 years. These included; age (relative risk of 1.63 per 6-year increase), serum cholesterol (relative risk 1.92 per 40 mg/dL increase), systolic blood pressure (relative risk of 1.32 per 20 mm Hg increase) and cigarette smoking (relative risk is 1.36 per 10 cigarette/day increases).31 Another study was performed to assess risk factors, extent and severity of coronary artery disease in 200 patients aged 35 years or younger who underwent diagnostic coronary angiography.11 Smoking (71%) and history of premature coronary artery disease (27%) were the 2 most frequent risk factors. History of previous ST elevation myocardial infarction (STEMI) was present in 68% of patients. Majority (54.5%) was treated conservatively and the rest (45.5%) required either percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). Smoking was the main risk factor in the previous study and it has also been supported by another report, where smoking is noted in 65% to 92% of young patients with myocardial infarction compared with 24% to 56% of patients older than 45 years.7 Younger patients with coronary artery disease more often have a family history of premature coronary artery disease. A higher incidence of positive family history in young patients (64%) was illustrated in the largest report of 823 patients.3 Obesity seems to be an independent risk factor for coronary atherosclerosis in young men. This was observed in a report from the Framingham Heart Study that suggests obesity in middle-aged patients may account for as much as 23% of cases with coronary artery disease in men and 15% in women.32 A recent published review in 2014 indicated that acute myocardial infarction in young patients almost exclusively occurs in males, with STEMI being the main diagnosis.33 Anterior wall myocardial infarction is the most common, with left anterior descending artery involvement in approximately two thirds of patients. The study included 124 patients diagnosed with myocardial infarction younger than 40 years with coronary angiography performed in all. Of 124 patients, 123 were men (mean age of 36). A total of 118 patients had STEMI (95%) and 6 with non-ST elevation myocardial infarction (NSTEMI) (6%). Anterior wall myocardial infarction was present in 88 patients (71%), inferior wall myocardial infarction in 31 (25%) and lateral wall myocardial infarction in 5 (4%). Significant coronary artery disease was found in 88 patients (71%) and 13 (10%) had normal coronaries. Single-vessel disease was observed in 57 patients (46%), 2-vessel disease in 15 (12%) and 3-vessel disease in 8 (6%). A total of 125 lesions were identified with left anterior descending artery which is the most common vessel involved with a total of 78 lesions (62%).34 Coronary artery disease in young adults carries a poor long-term prognosis as shown in a report, where 843 patients younger than 40 years diagnosed with coronary artery disease were identified and followed for 15 years.6 The strongest predictors of long-term mortality were; previous myocardial infarction (hazard ratio [HR] 1.32, 95% confidence interval [CI]
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1.00–1.73), New York Heart Association class II heart failure (HR 1.75, 95% CI 1.03–2.97) and active tobacco use (HR 1.59, 95% CI 1.14–2.21). Revascularization, rather than medical management, was associated with lower mortality (coronary angioplasty: HR 0.51, 95% CI 0.32–0.81; CABG: HR 0.68, 95% CI 0.50–0.94). However, overall mortality was 30% at 15 years. Patients with diabetes had 15-year mortality of 65%. Those with previous myocardial infarction had 15-year mortality of 45% and patients with an ejection fraction ,30% had 15-year mortality of 83%.34 In a prospective study, of over 7,000 women with a mean age of 27 years were followed for an average of 31 years, resulting in 47 coronary artery disease deaths.35 Coronary artery disease mortality rates for those with no risk factors, only 1 risk factor or 2 or more risk factors were 0.7, 2.4 and 5.4 per 1,000 person-years, respectively. A comparable relationship was observed for cardiovascular disease mortality and for allcause mortality.35
MANAGEMENT Acute Management Initial management of myocardial infarction in younger patients differs slightly from management in adults. Initial management with oxygen, morphine, nitrates and aspirin should be administered in all patients. In patients with positive history of cocaine use, beta-blockers must be delayed for 48 hours as it may result in severe coronary spasm and paradoxical worsening of chest pain. Benzodiazipines are recommended as the standard management of myocardial infarction in cocaine users, along with nitrates to counteract coronary spasm.36 Patients with cocaine-induced persistent ST elevation not resolved with nitrates should be offered thrombolytic therapy. In patients with persistent ST-segment elevation after nitrate and benzodiazepines, the 2007 ACC/AHA Task Force guidelines recommend the immediate coronary angiography and PCI, if indicated.37 Fibrinolytic therapy is an acceptable alternative only when timely coronary angiography is not possible.38 However, many patients with a history of cocaine use likely to be noncompliant for a long-term antiplatelet therapy. Therefore, the risk of stent thrombosis should be compared to the risk of conservative medical therapy and the choice should be made after pros and cons had been weighted. In addition, there is an increased rate of stent thrombosis with both bare metal stents and drug eluting stents (DESs) as reported in patients with cocaine-associated myocardial ischemia.39,40 So when a decision has been made to place a stent, bare metal stents should be chosen in preference to DESs.37 ST Elevation Myocardial Infarction Young patients with acute STEMI require revascularization either with primary PCI or, CABG if not available, thrombolytic therapy. The AHA recommends emergency CABG in the acute settings mainly (class I indication) in patients who failed PCI or when PCI cannot be performed; this is specifically recommended in those with suitable coronary anatomy and persistent ischemia or hemodynamic instability. CABG is also recommended in the acute setting when surgical intervention is indicated because of either acute papillary muscle dysfunction causing mitral regurgitation or in the case of myocardial rupture.41 Prospective randomized trials assessing primary PCI versus thrombolytic therapy for acute STEMI observed that both young and old patients have better outcomes with PCI compared with thrombolysis. However, younger patients have Volume 350, Number 6, December 2015
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superior outcomes compared with elderly, regardless of the therapy received. Irrespective of treatment, risk increases with age, after adjusting for baseline characteristics, as each increment of 10 years of age increased the risk of death or reinfarction by 1.32 times. Although data are limited, young patients also seem to respond well to thrombolytic therapy.42,43 In a study, clinical responses to streptokinase, as measured by TIMI II or III flow in an infarcted artery, were similar in patients younger than 35 and older than 55 years (74% versus 73%).42 Non-ST Elevation Myocardial Infarction Patients with a NSTEMI, NSTEMI or unstable angina are initially stabilized with medical therapy and should undergo early coronary angiography and revascularization, if appropriate. Higher risk patients should be referred to specialists to assess for early coronary angiography and intervention, if needed. Coronary angiography is not routinely offered in younger patients as significant numbers of patients tend to have normal coronary arteries. The efficacy of this approach is illustrated by the following study. One report evaluated 129 patients younger than 40 years, who had coronary angiography within 60 days of their 1st acute myocardial infarction.44 Patients without evidence of spontaneous or induced ischemia were compared to those who had ischemia or abnormal stress test after myocardial infarction. Conclusion was to offer early coronary angiography only for young patients with multiple risk factors or recurrent ischemia. Many other low-risk patients with uncomplicated course may undergo exercise stress testing as it is a simpler and more cost-effective modality for risk stratification before discharge. Echocardiographic assessment of left ventricular function is recommended in all patients.45 Chronic Management Management of stable angina, including indications for revascularization, is similar in both younger and older patients. Routine coronary angiography is not recommended in young patients who have stable coronary artery disease. However when indicated, both PCI and CABG are effective with lower risks in younger patients compared with elderly. Long-term outcome for young patients undergoing PCI is good.46,47 Success rates with percutaneous procedures were high in younger patients (93%). Ten-year overall and event-free survival without myocardial infarction, repeat PCI or elective CABG after PCI were 96% and 58%, respectively. Currently, DESs and glycoprotein IIb-IIIa inhibitors have success rates, which are expected to be higher with long-term studies pending.48 CABG is better performed in young patients as they are commonly in healthier physical condition compared with elderly and can better tolerate surgical stress with general anesthesia. CABG should be offered to patients with triplevessel disease, impaired left ventricular function and complex coronary artery abnormalities. Patients younger than 40 years were shown to have survival rates of 92% at 5 years and 86% in 10 years compared to 75% and 58% in patients older than 65 years.49 Arterial grafts are generally preferred to venous grafts because of longevity in patency as a study showed a survival rate of 91%, 74% and 50% at 5, 10 and 15 years, respectively, in patients younger than 40 years.50 In the nonacute setting and with multi-vessel disease, complete revascularization using bilateral internal mammary arteries (T-graft performed in 85% of patients) was shown to have less mortality compared with conventional CABG when Copyright © 2015 by the Southern Society for Clinical Investigation.
performed electively. To note, the study population age was younger than 70 years.51
PREVENTION Primary Prevention Despite little evidence addressing coronary artery disease prevention in young adults, decreasing modifiable risk factors remains the hallmark of reducing and preventing the disease. Lifestyle modification is significant in management of coronary artery disease and smoking cessation is strongly recommended. Extensive progression of CHD was noted in younger patients who continued to smoke after bypass surgery.43 Exercise and weight loss is recommended by American Heart Association as they were shown to increase high-density lipoprotein and decrease triglyceride levels. In addition, physical activity has been shown to improve endothelial function.52 Diabetes Control and Complications Trial indicated that patients with strict glycemic control in type 1 diabetes had less atherosclerosis, assessed by measuring carotid intima-media thickness.53 Control of diabetes and dyslipidemia was shown to have better prognosis in patients younger than 45 years. Risk factor modification may perhaps prove to be a challenging yet life-altering task in young population.54 Secondary Prevention Coronary artery disease in young patients carries a better prognosis, if appropriately managed. Poor risk factor control carries a significantly high morbidity and mortality.53 Medication management with antiplatelet agents such as aspirin and clopidogrel is essential. In addition, warfarin use is important in patients with coagulopathies and recurrent thrombotic events.48 Patients with suspicion for coronary spasm, beta-blocker administration must be delayed to prevent worsening of coronary vasoconstriction. Statins are invariably prescribed in patients with coronary artery disease as clinical benefits extend beyond lipid-lowering capabilities. Statins improve outcome and reduce recurrent events. Other agents such as niacin and omega 3 fatty acids should be considered in special circumstances as in low high-density lipoprotein levels and hypertriglyceridemia.55,56 Finally, angiotensin-converting enzyme inhibitors should be offered to all patients with left ventricular dysfunction as it has been approved in reducing mortality in this group of patients.57,58
CONCLUSIONS Cardiovascular disease is a leading health and economic burden as it is one of the leading causes of morbidity and mortality in middle-to-elderly aged population. Due to lack of symptoms in younger population, prevalence of coronary artery disease and CHD is yet to be accurately established. Different modifiable risk factors exist, such as smoking, obesity and dyslipidemia, which are strongly associated with the development of coronary artery disease. In younger adults, smoking is the most modifiable risk factor. Early detection, counseling and modifying risk factors are important in decreasing coronary artery disease and long-term complications in young adults. Moreover, awareness of uncommon risk factors such as coagulopathies and connective tissue disorders is essential in young adults. REFERENCES 1. Lloyd-Jones DM, Larson MG, Beiser A, et al. Lifetime risk of developing coronary heart disease. Lancet 1999;353:89.
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