Typical vs Atypical Ischemia

Once we consider it more likely than not that this patient had ischemic disease, the question of whether it was typical or atypical is somewhat more difficult to ascertain. First, it is necessary to define these two terms. Typical ischemic heart disease is generally considered secondary to coronary atherosclerosis, with atherosclerotic plaque (s) narrowing the lumen and causing damage to the coronary artery wall. The presence of atherosclerosis may increase the possibility of superimposed coronary artery lesions including acute plaque hemorrhage or rupture, luminal thrombosis, and/or coronary artery spasm. The presence of atherosclerosis does not provide information concerning the pathogenesis of the plaque, whether it is idiopathic but associated with cigarette smoking, hypercholesterolemia, hypertension, or diabetes mellitus (or combinations of all of these), or whether it may be secondary to less common risk factors such as hyperhomocysteinemia, cocaine use, or radiotherapy (chest irradiation for neoplastic disease).

Atypical ischemia is discriminated from typical angina pectoris, because it is considered to be non-atherosclerotic coronary artery disease. This implies different pathophysiological mechanisms, primarily secondary to coronary artery spasm, which may be spontaneous or caused by pharmacological agents including drugs such as cocaine. Other causes include hypercoagulable states, leading to coronary artery thrombosis; direct or indirect coronary artery infection (e.g. herpes virus or cytomegalovirus infection in immunosuppressed patients; salmonella infection of endothelial cells; or direct extension of bacterial infection from active endocarditis or pericarditis, leading to mycotic coronary artery aneurysm); mechanical disruption of the coronary artery, such as spontaneous or post-traumatic dissection (e.g. the trauma may be related to blunt force chest wall injury, or iatrogenic injury during interventions such as coronary angiogram or angioplasty); and finally, inflammatory diseases such as vasculitis. It is of particular importance to recognize that combinations of these various etiologies may occur simultaneously, making the assessment of the situation even more difficult.

Based on the previous definitions, did this patient have typical or atypical coronary artery ischemia? She was a relatively young woman. Atherosclerosis begins to increase in women in their fifth decade, but it is relatively uncommon unless they are postmenopausal, or affected by atypically high cholesterol levels or diabetes mellitus. Accelerated atherosclerosis, even in women with adequate ovarian hormonal function, can occur with hypercholesterolemia, diabetes mellitus, and rarely hypo-thyroidism with myxedema. We are not informed of this patient's menstrual history, a critical piece of information that is often not investigated during acute presentations with serious complaints in emergency rooms. However, it is reasonable to assume that at age 45 she was not postmenopausal. Moreover, she did not have a history of diabetes mellitus or hypertension. However, her physical examination did reveal a diffusely enlarged thyroid gland, but she had no complaints or physical signs of significant hypo or hyperthyroidism. Her serum cholesterol was low, which may even be secondary to hyperthyroidism, but it certainly rules out hypercholesterolemia. Despite this, she had a positive family history, with one sister (unknown whether she was older or younger) with coronary artery disease and myocardial infarction. Furthermore, the fact that her parents were alive and well, and a 50 year old brother was not reported to have coronary disease, strongly mitigate against the diagnosis of any familial condition that might have predisposed her to coronary artery disease. The significant smoking history put her at higher risk for coronary artery atherosclerosis, but it is rarely associated with this diagnosis in pre-menopausal women in the absence of hypercholesterolemia and hypertension.

Could there be any association with hepatitis B seropositivity? First of all, we are not informed whether she actually was infected previously, and if so, whether she was core or surface antigen positive. Regardless, there is no direct relationship with hepatitis B infection and coronary artery disease. There have been some loose associations with hepatitis B infection and the subsequent development of polyarteritis nodosa, but generally, most investigators do not consider this to be a convincing etiologic relationship. Polyarteritis nodosa is a vasculitis that can affect coronary arteries and could lead to ischemia with or without coronary thrombosis, but as an isolated event causing an acute presentation such as in this case, is very unlikely.

Could there be an association with her eleven year history of migraine headaches? This issue is somewhat more promising as an area of investigation. There have been cases of acute ischemic heart disease associated with several classes of agents used to treat migraine or vascular headaches. These include ergotamine derivatives, methysergide, and the newest class of serotonin receptor agonists. However, with all of these drugs that can potentially stimulate smooth muscle contraction and lead to coronary artery spasm, it is generally accepted that the rare coronary events are secondary to superimposed drug use in the presence of pre-existing coronary atherosclerosis. There are also anecdotal reports of patients with migraine headaches who have spontaneous coronary artery spasm, presumably due to hyper-reactivity of their coronary circulation. In the current case, there was no history of pre-existing migraine headache for which she had taken medication. Since patients with migraines are so exquisitely sensitive to their symptoms and affected by their condition, it is unlikely she would have not reported her symptoms or drug use, if she had had a migraine episode. Thus, it appears unlikely that migraine headaches, or their treatment, could explain her coronary ischemia. It is possible, however, that migraines could have been the etiology of the multiple episodes of syncope she reported previously.

Does the limited clinical information give us any additional clues, either positive or negative? There doesn't seem to be a condition associated with an increased tendency to thrombosis. There was no history of recurrent thromboemboli or thrombophlebitis. We are not informed as to whether she was using oral contraceptives, which might increase the risk of a thrombosis (along with smoking cigarettes). Her prothrombin time and partial thromboplastin time were completely normal, along with her platelet count. She was mildly anemic, but this is not associated with an increased tendency to thrombosis. Although we are not informed about her serum homocysteine levels, significant elevations of homocysteine are often associated with an increased thrombogenic tendency, and a higher risk for generalized development of atherosclerosis.

What about illicit drugs? One must always consider the possibility of prior or current drug use (specifically cocaine) in the context of a relatively young patient who should not be affected by typical coronary artery ischemia. Since cocaine is used by all strata of society as a recreational drug, it cannot be discounted regardless of socioeconomic class. Cocaine can affect the coronary circulation acutely or chronically, at any dose, and by any means of intake. Chronically, it can lead to damage of the vessel wall through hyperstimulation of vascular smooth muscle, endothelial damage, and subsequent atherosclerotic plaque development. Acutely, it can cause coronary artery spasm, either superimposed on a previously damaged vessel or in a normal vessel. In all circumstances, the mechanism is through binding to adrenergic receptors, leading to inhibition of catecholamine re-uptake at the neuromuscular junction, and subsequent increased contractile stimulation of smooth muscle. In this case, the patient was not asked specifically whether she had used cocaine previously, or shortly before her presentation; therefore, this possible cause for her symptoms cannot be assessed.

Two other etiologies have to be evaluated. Could this presentation be secondary to an inflammatory cause? There was no history or clinical findings consistent with a collagen vascular disease such as systemic lupus erythematosus, which may be associated with coronary artery vasculitis. She was not in the age-range of patients affected by Kawasaki disease (mucocutaneous lymph node syndrome, which is exclusively a pediatric condition), or temporal arteritis (a disease of the elderly, which as a giant cell arteritis can affect coronary arteries). She is in the appropriate age range for Takayasu's arteritis, but without other clinical complaints and with normal peripheral pulses, this is an extremely unlikely diagnosis. Could this be a mechanical event? Coronary artery dissection can occur in patients with connective tissue disorders such as Marfan's syndrome and Ehlers-Danlos syndrome, but both are generally associated with skin, joint, and skeletal abnormalities, in addition to a family history. Other connective tissue disorders, such as pseudoxanthoma elasticum, can lead to calcification and atheromatous plaque formation in the coronary artery; however this condition is usually associated with skin lesions. Spontaneous dissections also occur in pregnancy, or shortly after delivery. The current case had no such history. Rarely, coronary artery dissections occur spontaneously, without a history of iatrogenic intervention, trauma, pregnancy, or underlying connective tissue disorder.

Thus, we are left with a rapid onset of acute coronary ischemia in a relatively young woman, with no definite cause for her symptoms and sudden death. In this case, we can say that without an autopsy, the cause of her terminal events would remain a mystery, but would most likely be ascribed to coronary artery atherosclerosis. However, for a number of the reasons addressed above, it is more likely that the coronary artery ischemia was secondary to an atypical, non-atherosclerotic cause. The rapid course of her disease, and the failure of the admitting physicians to question her about her menstrual history and illicit drug use, makes the diagnosis not attainable on clinical grounds alone. Even if she had survived for a period of time after admission, it is not likely that a stress test or coronary angiography would have been able to pinpoint the etiology of her condition.

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