Myocardial infarction in the young
A Cengel, A Tanindi
Department of Cardiology, Gazi University, Faculty of Medicine, Besevler - 06500, Ankara, Turkey
Department of Cardiology, Gazi University, Faculty of Medicine, Besevler - 06500, Ankara
An increasing number of patients under 40 years of age are being hospitalized with the diagnosis of acute myocardial infarction. This is partly due to the increased prevalance of risk factors for atherosclerosis in the younger age group; especially increased incidence of impaired fasting glucose, high triglyceride, low high-density lipoprotein levels and increased waist to hip ratio. However, non-atherosclerotic coronary artery disease or hypercoagulability should also be investigated or at least suspected in the younger patients. The pathophysiology of different clinical conditions and disease states which cause acute coronary syndromes in the young patients are reviewed, and the diagnostic modalities and therapatic options for these conditions are briefly discussed by searching for «DQ»premature atherosclerosis«DQ», «DQ»hypercoagulable states«DQ», «DQ»risk factors for atherosclerosis in youth«DQ», «DQ»novel risk factors for atherosclerosis«DQ», «DQ»non-atherosclerotic coronary artery diseases«DQ» in PubMed.
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Cengel A, Tanindi A. Myocardial infarction in the young.J Postgrad Med 2009;55:305-313
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Cengel A, Tanindi A. Myocardial infarction in the young. J Postgrad Med [serial online] 2009 [cited 2021 Apr 18 ];55:305-313
Available from: https://www.jpgmonline.com/text.asp?2009/55/4/305/58944
Although myocardial infarction (MI) is usually the disease of people over 40 years of age, an increasing number of younger patients are being hospitalized with acute coronary syndromes. It brings significant physical and psychosocial morbidity. The increased prevalance in young adults can be partly attributed to the increased prevalance of risk factors for atherosclerosis among the population under the age of 40.  Besides atherosclerotic coronary artery disease, non-atherosclerotic coronary artery diseases or hypercoagulability should be considered for young cases of myocardial infarction. This article reviews the large spectrum of clinical conditions which result in myocardial infarction in young adults primarily by searching for "premature atherosclerosis", "hypercoagulable states", "risk factors of atherosclerosis in youth", "novel risk factors for atherosclerosis", "non-atherosclerotic coronary artery diseases" in PubMed [Table 1].
Non-Atherosclerotic Coronary Artery Disease
Congenital coronary abnormalities
In about 0.5% of patients undergoing coronary angiography, abnormal origin of coronary arteries are detected.  Some congenital coronary abnormalities may cause acute coronary syndromes while others remain undetected depending on the type and localization. Separate origin of the Left Anterior Descending (LAD) and Circumflex (Cx) arteries, origin of the Right Coronary Artery (RCA) from the left coronary sinus, and origin of the Cx from the right coronary sinus are the relatively frequent ones.  Coronary arteries originating from pulmonary artery, contralateral sinus or coronary arteriovenous fistula are the abnormalities which cause ischemia. These are detected on coronary angiography. Nowadays computed tomographic angiography (CTA) is thought to be superior to coronary angiography for the detection of congenital coronary abnormalities and hence preferred over coronary angiography. 
Connective tissue disorders
Connective tissue disorders cause myocardial damage by several mechanisms like coronary artery or aortic dissection, coronary artery aneurysm formation and thrombus formation.
Takayasu's arteritis is a granulomatous vasculitis of unknown etiology, which involves major branches of the aorta and pulmonary arteries, and rarely coronary arteries. In Takayasu's disease the average age for coronary artery disease presentation is reported to be 24 and usually the coronary ostia are involved.  Takayasu's arteritis presents as an isolated coronary lesion in less than 5% of the patients. Treatment modalities include pharmacological therapy with steroids and immunosuppressive agents, percutaneous coronary intervention with or without stent implantation or surgery. There is no consensus on the best strategy to treat coronary lesions to improve clinical outcomes. 
Giant cell arteritis (Temporal arteritis) is a chronic granulomatous vasculitis that affects mainly large and medium-sized vessels; most commonly temporal and vertebral arteries.  Not rarely atherosclerosis coexists with giant cell arteritis and usually favors the anterior component of polygon of Willis and the carotid system. Although coronary involvement is rare, there are case reports directly relating myocardial infarction with this vasculitis.
The leading cause of ischemic pain in children among acquired heart disease is Kawasaki's disease which causes acute myocardial infarction by coronary artery aneurysm and dissection.  Immunoglobulin and aspirin are the preferred agents for the acute phase. In some patients, after the acute phase, sclerotic vascular changes are observed even in the cases without coronary involvement at the acute disease. Peripheral vascular endothelial dysfunction has been observed in the post-Kawasaki disease patients in some recent studies and this vascular sequela is blamed for the early development of atherosclerosis. 
Patients with Systemic Lupus Erythematosus (SLE) are at increased risk for premature atherosclerosis.  Endothelial injury and dysfunction known to be the initiators of atherosclerosis are enhanced by immune complexes and complement activation in SLE. Complement activation can contribute to recruitment of monocytes, enhancement of migration into the arterial wall and stimulation of tissue factor which triggers pro-thrombotic state.  In SLE, autoantibodies to oxidized low-density lipoprotein (LDL) and antiphospholipid antibodies (APA) are produced. These autoantibodies recognize and bind to neoepitopes of oxidized LDL. This causes increased ingestion of oxidized LDL by macrophages. APA is known to have prothrombotic and atherosclerotic properties as well. In addition to these, CD 40 ligand which is an immunoregulatory co-stimulatory molecule involved in autoantibody formation is increased in SLE.
Although SLE is known to be associated with higher risk for acute myocardial infarction, post-infarction outcomes are less well studied. In a recent study, acute MI patients with SLE were found to have higher in-hospital mortality rates, so aggressive management and risk factor modification is logical for this group of patients. 
Coronary artery aneurysm-coronary dissection
Coronary dissection and aneurysm are rare but possible causes of myocardial infarction in young adults. They may be atherosclerotic, congenital, traumatic or mycotic in origin. Other causes are connective tissue disorders like Marfan or Ehler-Danlos or vasculitic disorders as mentioned before. Spontaneous coronary artery dissection is another rare cause of coronary ischemia and death. It is defined as coronary dissection in the absence of provoking factors like angiography, angioplasty and aortic dissection. The prevalance is higher in young females with a female to male ratio of 2:1. Although both right and left coronary arteries can be involved, LAD is more commonly affected, especially in female victims. This is mostly a disease of the peripartum period.  This is thought to be an inherited susceptibility to vascular degeneration under the hormonal and hemodynamic influences of pregnancy. The reported risk factors for spontaneous coronary dissection include oral contraceptives, cystic medial necrosis, fibromuscular dysplasia, a-1 Antitrypsin deficiency, immunosupressive therapy, weightlifting, intense aerobic exercise, hypertension, smoking and cardiac surgery. Atherosclerosis has also been blamed. The three-year mortality for patients who have survived the index event is about 20%.  Among females, mortality due to non-peripartum dissection is higher than the peripartum spontaneous dissection.
Myocardial bridging occurs between 0.5-16% on coronary angiography and between 15-85% on postmortem studies.  The coronary artery is anatomically covered by the myocardium and compressed at systole. Mid-portion of the LAD is involved most commonly. Rarely ischemia, infarction and arrythmias are reported.  How myocardial bridging causes ischemia has been a confusing entity since systolic compression should not affect the diastolic filling of the coronary artery. But recent studies have shown that the diastolic coronary diameter is also reduced in patients with myocardial bridging. Another aspect is the delayed opening of the coronary vessel after systolic compression so the inflow time is insufficient. It is also suggested that the elasticity is lost in patients with myocardial bridges who become symptomatic. Current treatment options include calcium channel blocker or beta blocker therapy, placement of intracoronary stent at the site of bridge, myotomy with unroofing of the bridge or coronary artery bypass graft (CABG) surgery. 
Radiation therapy to the mediastinum for the treatment of malignant disorders causes intimal damage, medial hypertrophy and adventitial scar formation. Subsequently this continuum may end up with myocardial ischemia and infarction.  Permanent complications occur rarely under the cumulative dose of 40 Gy and prevention is the best way to treat radiation-induced cardiotoxicity. Isolated discrete non-osteal coronary lesions may be suitable for percutaneous intervention. The rate of restenosis in radiation-induced coronary artery disease is thought to be similar to that in the general population although a direct comparison has not been done. Usually CABG is thought to be a better option. Still it should be kept in mind that surgery may also be difficult because of extensive fibrosis in the mediastinum. 
Illicit drug usage
Illicit drug abuse, especially using cocaine should be kept in mind when a young adult or a teenager is hospitalized for acute coronary syndrome. The pathogenesis includes an increased oxygen demand in the face of limited supply, marked vasoconstriction of the coronary arteries, and enhanced platelet aggregation. Cocaine-induced vasoconstriction is the result of the stimulation of a-adrenergic receptors. It also increases the potent vasoconstrictor endothelin and decreases nitric oxide (NO) production.  Cocaine also accelerates atherosclerosis by causing structural defects in the endothelial cell barrier, increasing its permeability to LDL and enhancing the expression of endothelial adhesion molecules and leucocyte migration.  In 130 patients in the Cocaine-Associated myocardial infarction study, 38% had cardiac complications, most of which were arrythmias. In another study with 24 cocaine-associated MI patients, recurrent ischemic events were reported to be 58%. 
Cessation of cocaine is the primary goal for secondary prevention, and aggressive risk factor modification is indicated. Timely percutaneous intervention is preferred over fibrinolytics in the setting of cocaine use since higher rates of intracranial hemorrhage are reported in drug abusers. 
Atherosclerotic Coronary Artery Disease
Classical risk factors
Atherosclerosis begins in childhood as cholesterol deposits, known as fatty streaks, in the intima of large arteries and it is accepted to be the precursor of raised lesions. The extent of coronary artery fatty streak in young people predicts the extent of raised lesions in older ages. The lesions start as lipid-laden macrophages with relatively normal intima and may convert to those containing extracellular lipid and cholesterol ester crystals with a collagenous and muscular cap (the fibrous plaque). 
In a postmortem study with 760 young adults, with the average age of 30-34; 20% of males and 8% of females were found to have atherosclerotic coronary artery disease.  In another study, cardiac transplant patients of average age 30-33 had undergone coronary angiography and intravascular ultrasound (IVUS). The prevalance of coronary artery disease was 50% and one in six teenage patients had coronary atherosclerotic lesions. 
In 1985, PDAY (Pathologic Determinants of Atherosclerosis in Youth) study was designed to investigate the risk factors for atherosclerosis in youth. Arteries, blood and selected tissues were collected from approximately 3000 people of 15-34 years of age who died within 72 h of injury, homicide or suicide and autopsied within 48 h.  About one half of the subjects were found to be smokers as indicated by serum thiocyanate concentration and 40% of the subjects had a BMI exceeding 25 and 10%, exceeding 30.
Smoking is found to be the most common risk factor in young coronary artery disease patients in other studies as well; reported as approximately 92%.  About 40% of the young coronary artery disease patients have first-degree relatives with premature atherosclerosis  and 65% have either overt diabetes or impaired glucose tolerance (IGT); in addition they are usually obese and very commonly meet the criteria of metabolic syndrome.
High LDL levels is one of the well-known predictors of cardiovascular events as reported elsewhere. LDL has multiple subclasses that differ in size, density, metabolic behaviour and atherogenicity.  LDL size emerged as a cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). Small dense LDL, elevated triglyceride levels and low HDL concentrations constitute the atherogenic lipoprotein phenotype (ALP); a form of atherogenic dyslipidemia which is a feature of Type II diabetes and the metabolic syndrome. The prevalence of small dense LDL is 30-35% in adult men and 5-10% in men under the age of 20. It is shown that LDL size is genetically influenced in an autosomal dominant or co-dominant fashion with different amounts of polygenic effects.  In family and twin studies, the heritability of LDL size phenotypes ranged from 40-60%. Small dense LDL is also related to the premature atherosclerosis in familial hyperlipoproteinemias like familial hypercholesterolemia. Diet, abdominal obesity and oral contraceptive use is known to affect the amount of small dense LDL. Smaller and denser LDL is taken up by the arterial intima more easily and the oxidative susceptibility is increased.
States of insulin resistance are associated with smaller LDL size and in diabetics LDL size is a good marker of clinically apparent or nonapparent atherosclerosis represented as increased carotis intima media thickness. Low HDL cholesterol levels are known to be associated with increased coronary artery disease risk and for each increase of 1 mg/dL in HDL, coronary artery disease risk decreases by 2-3%.  In addition to the concept of well-known reverse cholesterol transport, HDL has other antiatherogenic properties. It inhibits monocyte chemotaxis, leucocyte adhesion to the endothelium, endothelial dysfunction and apoptosis, LDL oxidation, and complement activation.  It stimulates prostacyclin and natriuretic peptide C in endothelial cells and activates protein C and S.
Fasting serum triglyceride levels are usually inversely related to HDL. In the literature, high triglycerides and low HDL are associated with increased insulin resistance, higher blood glucose even in the normal range, higher uric acid levels, hypertension and obesity.  There have been debates whether triglyceride levels are independently associated with cardiovascular risk. In a large meta-analysis of 17 trials between 1965 and 1994, data of 46,000 men and 11,000 women was evaluated and hypertriglyceridemia was found to be a risk factor for coronary heart disease.  NCEP ATP III indicated that hypertriglyceridemia was an independent risk beyond that predicted by LDL cholesterol alone. So it can be concluded that high triglycerides, which may be the primary lipid abnormality with or without low HDL levels and normal/low LDL levels in the young adults is a matter of concern.
Diabetes mellitus has been identified as an independent risk factor for susceptibility to coronary artery disease as reported elsewhere.  As previously mentioned, the number of young adults who have metabolic syndrome and insulin resistance has increased and impaired fasting glucose or impaired glucose tolerance is more prevalant at younger ages today. There is increasing evidence that lesser degrees of hyperglycemia is associated with atherosclerosis. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are different categories of abnormal glucose metabolism.  In a meta regression analysis of cohort studies, a graded relation was reported between the fasting and postprandial glucose levels below diabetic threshold and the 12-year cardiovascular event incidence. 
The International Diabetes Federation reported that IFG is characterized by raised hepatic glucose output and deficits in early insulin secretion while IGT is characterized by peripheral insulin resistance.
An acute elevation in the blood glucose adversly affects endothelial function most probably by reduced production and bioavailability of nitric oxide. In addition, platelet aggregation is enhanced and tendency to coagulation is increased as indicated by shortened fibrinogen half life, increased fibrinopeptide A and Factor VII levels. 
Acute hyperglycemia is a powerful stimulus in both the normal subjects and the ones with impaired glucose metabolism, for inflammatory mediators, cytokines and adhesion molecules like ICAM-1 which have well-defined roles in atherosclerosis.  Endothelial dysfunction has a reciprocal relationship with insulin resistance. In a study by Tesauro et al., significant endothelial dysfunction, insulin resistance and elevated levels of markers of inflammation were detected in the normoglycemic offsprings of patients with Type II diabetes mellitus. 
Emotional stress and agressive nature in the young age group are thought to be related to the prevalance of coronary artery disease. In the CARDIA study the "hostility index" score was found to be directly related to the presence of coronary artery calcification. 
The presentation in the young age group is usually acute myocardial infarction or unstable coronary syndrome whereas stable coronary disease remains at about 20%.  Acute physical or emotional stress which results in an increase in shear forces causes a previously non-significant plaque to rupture and leads to acute myocardial infarction. These patients usually benefit quite well from revascularisation. Unfortunately, the young multivessel patients with hyperlipidemia and diabetes in the background benefit in a limited fashion and in the long term, prognosis is worse compared to the other group. 
Patients with premature atherosclerosis and their first-degree relatives have higher levels of lipoprotein (a).  This hepatic origined protein which is thought to be related with premature atherosclerosis is a genetic variant of LDL which includes apolipoprotein (a). The apolipoprotein B100 is linked by a disulfide bond to apolipoprotein (a).
In several studies, children under 18 years of age who have premature atherosclerosis in their family are found to have two to three times higher lipoprotein (a) levels.  Lipoprotein (a) is readily oxidized and forms highly atherogenic particles with LDL and it enhances oxidation uptake and retention. It also promotes the lipid uptake by the macrophages. Lipoprotein (a) is structurally similar to plasminogen which is another liver-derived protein. Lipo(a) competes with plasminogen for binding to receptors in endothelial cells, mononuclear cells, platelets, fibrinogen and fibrin. Lipo(a) enhances thrombosis by decreasing plasmin formation, impairing fibrinolysis, inhibiting t-PA and enhancing production of PAI-1. In addition to promotion of thrombin formation, it increases smooth muscle proliferation and migration, enhances intracellular adhesion molecules and impairs collateral formation. 
Lipoprotein(a) appears to be a risk factor limited to premature atherosclerosis, it is strongest before age 45, and impact of lipo(a) elevation is not uniform in terms of race with the highest rate in Asian Indians.  The predictivity of lipo(a) increases in high-risk groups, diabetic and hyperlipidemic patients. It is used more reliably in hyperfibrinogenemia and hyperhomocysteinemia as well. There are differences in the assays used for lipo(a) measurement. In addition, there is no efficient method to decrease its levels other than Niacin therapy. The reduction in lipoprotein (a) levels provide no benefit over LDL reduction Considering all these, lipoprotein(a) is not currently routinely recommended to be measured as a risk determinant.
Primary or secondary dyslipidemias leads to premature atherosclerosis by causing excess deposition of cholesterol in tissues. Familial hypercholesterolemia (FH) is inherited autosomal dominantly; the incidence is 1 in 1 million for homozygotes and 1 in 500 for heterozygotes.  Premature atherosclerosis is four to six times more frequent in the heterozygote patients, whereas the risk of facing a fatal MI under the age of 20 for the homozygote patients is approximately 100%. On the molecular basis, mutation in the LDL receptors, dysfunctional LDL receptors or decrease in the hepatic LDL clearance can be responsible. Total cholesterol levels of heterozygotes are about 300-400 mg/dl and the LDL levels are about 200-300 mg/dl, but in the homozygous individuals total cholesterol and LDL levels of up to 600 mg/dl are possible. 
Familial combined hyperlipidemia (FCHL) is the most common primary dyslipidemia where multiple lipoprotein phenotype is observed. It is usually diagnosed after 20 years of age and it constitutes about ¼ - ½ of familial coronary artery disease and 20% of premature coronary artery disease. Diabetes mellitus, insulin resistance, obesity and hypertension are very commonly observed. In addition to high levels of LDL, total cholesterol and triglyceride and low levels of HDL; Apo B100 levels are higher than 120 mg/dl and small dense LDL particles are predominant. 
In a recent study, 102 MI survivors under 40 years of age were searched for the prevalance of familial combined hyperlipidemia and familial hyperlipidemia. Thirty-eight per cent displayed FCHL phenotype which was a higher ratio compared with other studies; whereas 8% were classified as possible or definitive FH, and this ratio was similar to other studies which enrolled young MI survivors. FCHL phenotype was associated with 24-fold increased adjusted risk for MI (95% CI 7.5-81, P 
Other dyslipidemias that are related to premature atherosclerosis are familial defective apolipoprotein B100, polygenic hypercholesterolemia, hyperabetalipoproteinemia, Type 3 hyperlipidemia (familial dyslipidemia). Secondary dyslipidemias are most commonly related to diet, drugs (oral contraceptives, hormone replacement therapy, steroid), hypothyroidism and other endocrine disorders, hepatic dysfunction, obesity and smoking.
Should young MI survivors be investigated for acquired or congenital hypercoagulability syndromes is not a matter of certainty. But if a strong thrombophilia is detected such as homozygous FV Leiden, protein C deficiency, antiphospholipid antibody syndrome, antithrombin III deficiency; long-term anticoagulation should be considered for a patient who has suffered a non-atherosclerotic thromboembolic event. 
Factor V Leiden
Factor V Leiden is the most common inherited thrombophilia with an incidence of about 5%.  The risk of venous thrombosis is increased 50-80 times in the homozygotes and three to five times in the heterozygotes. Approximately 20-40% of venous thromboembolic patients are known to suffer the condition. Activated protein C acts as an anticoagulant by cleaving multiple bonds and destroying the membrane-bound activated forms of coagulation Factors V and VIII, using protein S as the cofactor. By a mutation taking place in the FV gene, arginine is replaced by glutamine in the aminoacid position 506 which is one of the cleavage sites of activated protein C. Generally, Factor V Leiden is not considered as a major risk factor for MI or cerebrovascular accident but it was identified as a significant risk factor for MI in young smoking women.  In a study searching for the prognostic significance of having Factor V Leiden mutation in the AMI survivors, no increase in the rates of reinfarction, heart failure or post infarction angina were reported. 
Activated protein C resistance is sometimes acquired in pregnancy or with hormone therapy and antiphospholipid antibody syndrome. In the meta-analysis of 33 studies with 25053 patients, the relative risk for MI was 1.10 (95%CI, 0.88-1.36), for ischemic serebrovascular accident 1.27 (95% CI, 0.86-1.87), and for peripheral vascular disease 0.91 (95% CI; 0.38-2.16). Patients over 55 years of age were found to be affected more than the young patients in terms of clinical event rates. 
Prothrombin G20210A gene mutation
The prothrombin G20210A gene which is found in 1-6% of whites is prone to polymorphism. In the presence of other inherited or acquired risk factors, the venous thrombosis is two to three times more frequent. It is generally thought that inherited thrombophilias and arterial thrombosis have no association in the general population but inconsistent results have been reported in the literature. In a recent meta-analysis, the relationship between PT G20210A mutation and MI or ischemic cerebrovascular accident was found to be nonsignificant; the relative risks were 1.28 (95% CI, 0.94-1.73) and 1.3 (95% CI, 0.91-1.87) respectively.  It cannot be neglected that there may be an influence in selected populations such as young patients with no predisposing risk factors.
Antithrombin III deficiency
Antithrombin III deficiency can be inherited in an autosomal dominant fashion and caused by mutations in the antithrombin gene, or can be acquired as a consequence of variety of diseases like disseminated intravascular coagulation, nephrotic syndrome or renal failure.  It increases mainly the risk of venous thrombosis. Relative risk is reported to be about 8; but may increase up to 20-fold when other acquired risk factors are present as well. Although rare cases of arterial thrombosis are reported,  routine evaluation is not recommended since antithrombin III deficiency was not described as a risk factor in larger scale studies.
Protein C and protein S deficiency
Protein C and S deficiency can be inherited or acquired in hepatic diseases, Warfarin use, inflammatory conditions, pregnancy, hormone therapy. Venous thrombosis is increased about 10-fold in the heterozygote individuals. As in antithrombin III deficiency, arterial thrombosis is very rarerly reported in the literature and it is not clear whether it may increase arterial thrombosis risk. 
Hyperhomocysteinemia is an independent risk factor for ischemic cardiovascular disease, peripheral vascular disease and stroke. Up to 40% of patients diagnosed with premature coronary artery disease, peripheral vascular disease or recurrent venous thrombosis are detected to have hyperhomocysteinemia.  Endothelial dysfunction and apoptotic death of endothelial and smooth muscle cells are the two main mechanisms of how homocystein causes premature atherosclerosis. Apoptosis of the smooth muscle cells leads to a decrease in the collagen synthesis and decrease in the fibrous cap production consequently. This causes instability of the plaque and the tendency to thrombosis is increased. 
Four enzymes are responsible for the homocystein metabolism: Cystathionin ß-synthase, Methionine synthase, 5,10 MTHFR, Betaine-homocysteine methyl transferase. The gene mutations related to these enzymes cause severe hyperhomocysteinemia and even homocystinuria. The most common enzyme deficiency among these is the deficiency of cystathionine ß-synthase which causes a syndrome presenting with mental retardation, ectopia lentis, osteoporosis, skeletal abnormalities, hepatic steatosis and death, generally due to cardiovascular diseases. Among the acquired causes of hyperhomocysteinemia are most commonly dietary insufficiency, especially of vitamin B6, B12 and folic acid and renal failure. Although homocystein levels can be decreased with vitamin supplementation, it is not generally recommended since no cardiovascular benefit is demonstrated.
Hyperhomocysteinemia impairs endothelial nitric oxide (eNO)-dependent vasodilation but the expression of endothelium-derived nitric oxide synthase (NOS) and the vasodilator response to Nitroglycerin or Nitroprusside is preserved.  There is a decrease in the bioavailability of NO. The decrease in NO bioavailability has been attributed to inactivation of eNO by reactive oxygen radicals such as superoxide, hydrogen peroxide or peroxynitrite and to the increase in the levels of asymmetric dimethylarginine (ADMA), which is known as an inactivator of eNOS. By Methionin loading, ADMA catabolism is impaired and the levels are increased.
Homocystein adversly affects the endothelium by provoking proinflammatory changes. It causes increased expression of IL-8 and MCP-1 (monocyte chemotactic protein) through activation of NF-kB (nuclear factor) which is a transcription factor known to stimulate cytokine, chemokine and leukocyte adhesion molecule expression. MCP-1 enhances binding of monocytes to the endothelium and recruitment in the subendothelial space, and IL-8 is a chemoattractant for neutrophils and T lymphocytes. 
Methylene tetrahydromethylene reductase (MTHFR) is an enzyme which takes place in the homocystein metabolism. In a meta-analysis, the relative risk for MI when there was a mutation in the MTHFR gene was 1.05 (95% CI, 0.86-1.27), and for ischemic cerebrovascular accident, relative risk was 1.46 (95% CI, 1.19-1.79). There is no specific study for peripheral vascular disease. 
Antiphospholipid antibody syndrome
Antiphospholipid antibody syndrome is one of the most common acquired thrombophilias. Antiphospholipid antibodies are produced against phospholipid binding proteins or cardiolipin. Either arterial or venous thrombosis is possible. When these antibodies occur due to induction by infections or drugs they cannot be correlated with increased risk of thrombosis.  Some studies have observed that the condition is associated with an increased risk of MI. Ideally, young patients with MI should undergo primary angioplasty, but thrombolysis was found to be effective in establishing coronary blood flow adequately as well. In the secondary prophylaxis, high-dose oral anticoagulation is generally recommended since standard antiplatelet regimens are ineffective for prevention of recurrent thrombotic episodes. 
How to proceed after the routine urgent management of acute MI is completed in a young MI survivor? [Figure 1]
First of all, search for the classical risk factors for atherosclerosis Although various clinical entities are described in the text, it should be kept in mind that the well-known classical risk factors for atherosclerosis remain the leading cause for coronary artery disease in every age group as recently published in the INTERHEART study as well. For the younger patients, low HDL, high TG levels, impaired fasting glucose, increased waist to hip ratio are especially worth mentioning.Consider illicit drug use which may cause predominantly vasospastic MIConsider congenital coronary abnormalities, coronary aneurysm, coronary dissection These should be kept in mind especially for very young MI survivors. Coronary angiography is the gold standard for the diagnosis, sometimes CT angiography may be needed especially for the congenital cases. Prompt management, usually surgical treatment is necessary thereafter.Consider connective tissue disorders and vasculitic syndromes. Especially coronary artery dissection or aneurysm formation should raise the suspicion of vasculitis or connective tissue disorders. History and physical examination are the cornerstones for diagnosis. Fever, arthritis, skin rash, hematologic, renal or neurologic impairment as well as abscence of major peripheral pulses with or without hypertension are quite indicative of vasculitic syndromes.Search for hypercoagulability Factor V Leiden, prothrombin gene mutation, hyperhomocysteinemia, MTHFR gene mutation, antiphospholipid antibody syndrome and some other disorders are easily diagnosed by simple blood drawing for biochemical and genetic laboratory assessment.
|1||Egred M, Viswanathan G, Davis GK. Myocardial infarction in young adults. Postgrad Med J 2005;81:741-5.|
|2||Harikrishnan S, Jacob SP, Tharakan J, Titus T, Kumar VK, Bhat A, et al. Congenital coronary anomalies of origin and distribution in adults: A coronary angiographic study. Indian Heart J 2002;54:271-5.|
|3||Crean A. Cardiovascular MR and CT in congenital heart disease. Heart 2007;93:1637-47.|
|4||Endo M, Tomizawa Y, Nishida H, Aomi S, Nakazawa M, Tsurumi Y, et al. Angiographic findings and surgical treatments of coronary artery involvement in Takayasu arteritis. J Thorac Cardiovasc Surg 2003:125:570-7.|
|5||Araszkiewicz A, Prech M, Hrycaj P, Lesiak M, Grajek S, Cieslinski A. Acute myocardial infarction and rapid development of coronary aneurysms in a young woman-unusual presentation of Takayasu arteritis? Can J Cardiol 2007;23:61-3.|
|6||Godoy P, Araujo Sde A, Paulino E Jr, Lana-Reixoto MA. Coronary giant cell arteritis and acute myocardial infarction. Arq Bras Cardiol 2007;88: E84-7.|
|7||Soga T, Uemura S. Cardiovascular and the other complication followed with Kawasaki disease. Nippon Rinsho 2008;66:289-95.|
|8||Fukazawa R, Ogawa S. Long-term prognosis of patients with Kawasaki disease: At risk for future atherosclerosis? J Nippon Med Sch 2009;76:124-33.|
|9||Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger Jr TA, Jansen-Mc Williams L, et al. Age-specific incidence rates of myocardial infarction and angina in women with SLE. Am J Epidemiol 1997;145:408-15.|
|10||Rhew EY, Ramsey-Goldman R. Premature atherosclerotic disease in systemic lupus erythematosus - role of inflammatory mechanisms. Autoimmun Rev 2006;5:101-5.|
|11||Shah MA, Shah AM, Krishnan E. Poor outcomes after acute myocardial infarction in systemic lupus erythematosus. J Rheumatol 2009;36:570-5.|
|12||Madu EC, Kosinsky DJ, Wilson WR, Burket MW, Fraker TD Jr, Ansel GM. Two-vessel coronary artery dissection in the peripartum period: Case report and literature review. Angiology 1994;45:809-16.|
|13||Longheval G, Badot V, Cosyns B, Najioullah S. Spontaneous coronary artery dissection: Favorable outcome illustrated by angiographic data. Clin Cardiol 1999;22:374-5.|
|14||Rossi L, Dander B, Nidasio GB, Arbustini E, Paris B, Vassanelli C, et al. Myocardial bridges and ischemic heart disease. Eur Heart J 1980;1:239-45.|
|15||Patane S, Marte F, Patane F, Di Bella G, Chiofalo S, Cinnirella G, et al. Acute myocardial infarction in a young patient with myocardial bridge and elevated levels of free triiodothyronine. Int J Cardiol 2009;132:140-2.|
|16||Zurick AO 3rd, Klein JL, Stouffer GA. Scintigraphic evidence of severe myocardial hypoperfusion in a patient with left anterior descending coronary artery bridging-case report and review of the literature. Am J Med Sci 2008;336:498-502.|
|17||Virmani R, Farb A, Carter AJ, Jones RM. Comparative pathology: Radiation induced coronary artery disease in man and animals. Semin Interv Cardiol 1998;3:163-72.|
|18||Adams MJ, Hardenbergh PH, Constine LS, Lipshultz SE. Radiation-associated cardiovascular disease. Crit Rev Oncol Hematol 2003;45:55-75.|
|19||Wilbert-Lampen U, Seliger C, Zilker T, Arendt RM. Cocaine increases the endothelial release of immunoreactive endothelin and its concentrations in human plasma and urine: Reversal by coincubation with sigma receptor antagonists. Circulation 1998:98;385-90.|
|20||Kolodgie FD, Wilson PS, Mergner WJ, Virmani R. Cocaine-induced increase in the permeability function of human vascular endothelial cell monolayers. Exp Mol Pathol 1999;66:109-22.|
|21||Hollander JE, Hoffman RS. Cocaine-induced myocardial infarction: An analysis and review of the literature. J Emerg Med 1992;10:169-77.|
|22||Mc Cord J, Jneid H, Hollander JE, de Lemos JA, Cercek B, Hsue P et al. Management of cocaine-associated 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;117:1897-907.|
|23||Stary HC, Chandler AB, Glagov S, Guyton JR, Insull W Jr, Rosenfeld ME, et al. A definition of initial, fatty streak and intermediate lesions of atherosclerosis: A report from the Commitee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler 1994;14:840-56.|
|24||McGill HC Jr, McMahan CA, Zieske AW, Tracy RE, Malcom GT, Herderick EE, et al. Association of coronary heart disease risk factors with microscopic qualities of coronary atherosclerosis in youth. Circulation 2000;102:374-9.|
|25||Tuzcu EM, Kapadia SR, Tutar E, Ziada KM, Hobbs RE, McCarthy PM, et al. High prevalance of coronary atherosclerosis in teenagers and young adults: Evidence of intravascular ultrasound. Circulation 2001;103:2705-10.|
|26||Wissler RW. USA multicenter study of the pathobiology of atherosclerosis in youth. Ann N Y Acad Sci 1991;623:26-39.|
|27||Zimmerman FH, Cameron A, Fisher LD, Ng G. Myocardial infarction in young adults: Angiographic characterization, risk factors and prognosis (Coronary Artery Surgery Study). J Am Coll Cardiol 1995;26:654.|
|28||Chen L, Chester M, Kaski JC. Clinical factors and angiographic features associated with premature coronary artery disease. Chest 1995;108:364-9.|
|29||Rizzo M, Rini GB, Berneis K. The Clinical relevance of LDL size and subclasses modulation in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes 2007;115:477-82.|
|30||Austin MA. Genetic epidemiology of low-density lipoprotein subclass phenotypes. Ann Med 1992;24:477-81.|
|31||Boden WF. High-density lipoprotein cholesterol as an independant risk factor in cardiovascular disease: Assessing the data from Framingham to the Veterans Affairs High-Density Lipoprotein Intervention Trial. Am J Cardiol 2000;86:19L-22L.|
|32||Negre-Salvayre A, Dousset N, Ferreti G, Bacchetti T, Curatola G, Salvayre R. Antioxidant and cytoprotective properties of high-density lipoproteins in vascular cells. Free Radic Biol Med 2006;41:1031-40.|
|33||Castelli WP. The triglyceride issue: A view from Framingham. Am Heart J 1986;112:432-7.|
|34||Cullen P. Evidence that triglycerides are an independant coronary heart disease risk factor. Am J Cardiol 2000;86:943-9.|
|35||Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events: A meta-regression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 1999;22:233-40.|
|36||Peterson JL, McGuire DK. Impaired glucose tolerance and impaired fasting glucose: A review of diagnosis, clinical implications and management. Diabetes Vasc Dis Res 2005;2:9-15.|
|37||Sudic D, Razmara M, Forslund M, Ji Q, Hjemdahl P, Li N. High glucose levels enhance platelet activation: Involvement of multiple mechanisms. Br J Haematol 2006;133:315-22.|
|38||Marfella R, Esposito K, Guinta R, Coppola G, De Angelis L, Farzati B, et al. Circulating adhesion molecules in humans: Role of hyperglycemia and hyperinsulinemia. Circulation 2000;101:2247-51.|
|39||Tesauro M, Rizza S, Iantorno M, Campia U, Cardillo C, Lauro D, et al. Vascular, metabolic and inflammatory abnormalities in normoglycemic offspring of patients with type 2 diabetes mellitus. Metabolism 2007;56:413-9.|
|40||Iribarren C, Sidney S, Bild DE, Liu K, Markovitz JH, Roseman JM, et al. Association of hostility with coronary artery calcification in young adults: The CARDIA study: Coronary artery risk developement in young adults. JAMA 2000;283:2546-51.|
|41||Fournier JA, Sanchez A, Quero J, Fernandez-Cortacero JA, Gonzalez-Barrero. Myocardial infarction in men under 40 years or less: A prospective clinical-angiographic study. Clin Cardiol 1996;19:631-6.|
|42||Bostom AG, Cupples LA, Jenner JL, Ordovas JM, Seman LJ, Wilson PW, et al. Elevated plasma lipoprotein(a) and coronary heart disease in men aged 55 years and younger: A prospective study. JAMA 1996;276:544-8.|
|43||Wilcken DE, Wang XL, Greenwood J, Lynch J. Lipoprotein(a) and apolipoproteins B and A-1 in children and coronary vascular events in their grandparents. J Pediatr 1993;123:519-26.|
|44||Hajjar KA, Nachman RL. The role of lipoprotein(a) in atherogenesis and thrombosis. Annu Rev Med 1996;47:423-42.|
|45||Enas EA. Lipoprotein(a) is an important genetic risk for coronary artery disease in Asian Indians. Am J Cardiol 2001;88:201-2.|
|46||Hopkins PN. Familial hypercholesterolemia: Improving treatment and meeting guidelines. Int J Cardiol 2003;89:13-23.|
|47||Goldstein JL, Schrott SG, Hazzard WR, Bierman EL, Motulsky AG. Hyperlipidemia in coronary heart disease: II: Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest 1973;52:1544-68.|
|48||Wiesbauer F, Blessberger H, Azar D, Goliasch G, Wagner O, Gerhold L, et al. Familial-combined hyperlipidemia in very young myocardial infarction survivors(< or=40 years of age). Eur Heart J 2009;30:1073-9.|
|49||Foy P, Moll S. Thrombophilia: 2009 update. Curr Treat Options Cardiovasc Med 2009;11:114-28.|
|50||Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: A clinical perspective. Ann Intern Med 1997;127:895.|
|51||Juul K, Tybjaerg-Hansen A, Steffensen R, Kofoed S, Jensen G, Nordestgaard BG. Factor V Leiden: The Copenhagen City Heart Study and 2 metaanalysis. Blood 2002;100:3-10.|
|52||Baykan M, Celik S, Ucar F, Kaplan S, Ovali E, Erdol C. Effects of factor V Leiden mutations on prognosis in patients with acute myocardial infarction. Anadolu Kardiyol Derg 2001;1:242-5.|
|53||Kim RJ, Becker RC. Association between factor V Leiden, prothrombinG20210 A and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: A meta-analysis of published studies. Am Heart J 2003;146:948-57.|
|54||Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism-results of the Spanish Multicentric Study on Thrombophilia (EMET study). Thromb Haemost 1997;77:444-51.|
|55||Shimizu K, Toriyama F, Ogawa F, Katayama I, Okajima K. Recurrent leg ulcers and arterial thrombosis in a 33 year old homozgous variant of antithrombin. Am J Hemotol 2001;66:285-91.|
|56||Koster T, Rosendaal FR, Briet E, van der Meer FJ, Colly LP, Trienekens PH, et al. Protein C deficiency in a controlled series of unselected outpatients: An infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood 1995;85:2756-61.|
|57||Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B, et al. Hyperhomocysteinemia: An independant risk factor for vascular disease. N Engl J Med 1991;324:1149-55.|
|58||Zhang C, Cai Y, Adachi MT, Oshiro S, Aso T, Kaufman RJ, et al. Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. J Biol Chem 2001;276:35867-74.|
|59||Lentz SR. Homocysteine and cardiovascular physiology in Homocysteine in Health and disease. In: Cormel R, Jacobson DW, editors. Cambridge UK: Cambridge University Press; 2001.|
|60||Poddar R, Sivasubramanian N, Di Bello PM, Robinson K, Jacobsen DW. Homocysteine induces expression and secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells: Implications for vascular disease. Circulation 2001;103:2717-23.|
|61||Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295-306.|
|62||Davies JO, Hunt BJ. Myocardial infarction in young patients without coronary atherosclerosis: Assume primary antiphospholipid syndrome until proved otherwise. Int J Clin Pract 2007;61:379-84.|