Acute Myocardial Infarction in a Patient with Pheochromocytoma and Neurofibromatosis

Elevated plasma catecholamine levels associated with pheochromocytoma may cause myocardial injury in the absence of clinically significant atherosclerotic coronary artery disease. The cardiovascular manifestations of pheochromocytoma are diverse, making early diagnosis challenging. Nevertheless, quick diagnosis is imperative in order to initiate proper therapy. We present the case of a patient with extra-adrenal pheochromocytoma presenting as an acute myocardial infarction. Case Report. A 36-year-old Asian male with no significant past medical history presented to the emergency department of a community hospital after experiencing 24 hours of intermittent but intensifying bilateral mid-to-lower back and abdominal pain associated with nausea, dry heaving, vomiting, palpitations and diaphoresis. The patient reported no use of illicit drugs and no family history of coronary artery disease. Upon initial physical examination the patient was in moderate distress, with blood pressure 224/135 mm Hg and heart rate 147 bpm. Carotid pulsations were bounding. Heart examination was significant for tachycardia, prominent palpable apical impulse, easily audible heart sounds with no murmurs or gallops. There were multiple subcutaneous and cutaneous superficial neurofibromas over face, trunk, upper extremities, sparing the lower extremities and mucosal areas. There were several large café au lait spots over lower extremities and back (Figure 1). There was no reported family history of similar dermatological findings. Laboratory data noted white blood cell count 21000 cells/mm3 and hemoglobin 17g/dl. Initial ECG showed sinus tachycardia with frequent ventricular premature beats (including ventricular bigeminy) and a marked pattern of acute injury with up to 12mm ST segment elevation throughout the precordial leads (V2–V6) and 5mm ST segment elevation in the inferior leads (II, III, aVF) (Figure 2). Serial changes of evolving myocardial infarction were noted on subsequent ECG tracings (Figure 3). Initial CPK was 80U/mL in the emergency department he received intravenous metoprolol, aspirin and heparin. The tachycardia did not improve and systolic blood pressure increased to 250 mmHg. The patient then complained of chest pain. He was transferred to our institution, a tertiary care facility, for urgent coronary angiography and possible primary percutaneous coronary intervention in the presence of suspected acute myocardial infarction. Coronary angiography revealed normal coronary arteries (Figure 4) with no angiographic evidence of atherosclerosis. Left ventriculography was significant for severe and extensive anteroapical hypokinesis (Figure 5). Subsequent bedside echocardiography performed upon arrival to the coronary care unit confirmed severe segmental left ventricular dysfunction. Overall LV ejection fraction was 36%. Right ventricular size and function were normal. The presenting signs and symptoms resolved over the next few hours. Peak serum cardiac enzymes revealed a troponin I of 11 U/mL with a CPK of 369U/mL and an MB fraction of 7%. Myocardial injury was evident with segmental wall motion abnormalities despite normal coronaries on angiography. Pheochromocytoma was suspected as part of neurofibromatosis type I syndrome. Elevated catecholamines with resulting vasospasm were suspected as the cause of myocardial infarction. The patient was placed on low doses of phenoxybenzamine and labetalol with subsequent normalization of blood pressure, resolution of tachycardia and symptoms. MRI of the abdomen revealed a heterogeneous 46 x 50 mm retroperitoneal mass adjacent to the left adrenal gland (Figure 6). The right adrenal gland appeared normal and no other lesions were observed. Twenty-four hour urine studies found catecholamines to be significantly elevated with predominantly norepinephrine (693mcg/day, normal range: 15–100mcg/day). An I-131 metaiodobenzylguanidine (MIBG) scan showed functional tracer uptake corresponding to the region noted on the MRI. Repeat echocardiography 72 hours after original presentation revealed resolution of all wall motion abnormalities and estimated EF 62%. Subsequent hospital course was unremarkable, without any recurrent hypertensive crises. He was discharged home on an alpha-receptor antagonist (phenoxy-benzamine), beta-blocker (labetalol), and aspirin. Five weeks later the patient underwent excision of the mass. Intraoperative findings were significant for a large left para-aortic mass adherent to the anterior aorta, left renal artery and left renal vein with branches of left renal vein being encased by the mass. The left adrenal gland appeared normal and was not excised. Histopathology revealed a poorly differentiated epithelial tumor (Figure 7) with extensive necrosis on immunohistochemical stains, supporting the diagnosis of malignant pheochromocytoma. The tumor was successfully excised and postoperative urinary catecholamines normalized. Discussion. Most pheochromocytomas (90%) are benign tumors of chromaffin cells that produce systemic manifestations by secretion of catecholamines. Although most cases are found in the adrenal gland (80%) they also may be found in extra-adrenal tissues derived from neural crest cells. When found outside the adrenal gland they are more likely to be malignant (30%) as was the case above. Most pheochromocytomas (90%) are sporadic. Familial predisposition is seen in patients with multiple endocrine neoplasia type II (MEN II), von Hippel-Lindau disease and neurofibromatosis type I (von Recklinghausen’s disease). Pheochromocytoma is rare in patients with neurofibromatosis type I and is reported in only 0.1–1% of the cases. Nevertheless, 4–25% of patients with pheochromocytoma are reported to have a concurrent incidence of neurofibromatosis type I.¹Hypertension, either sustained or paroxysmal, is the most frequent cardiovascular manifestation of pheochromocytomas, with reviews placing its frequency as high as 72.4%.² Despite the low prevalence of the condition, its hallmark (severe, labile blood pressure elevation) leads to a rather frequent consideration as a potential etiology in young severely hypertensive patients. Nonetheless, pheochromocytoma frequently does not present in what is often described as its classic manifestation, making a prompt recognition more challenging.³ For example, in patients with predominantly epinephrine producing tumors, the beta effect on peripheral vasculature may explain the atypical manifestation of the hypotension observed.⁴ In this case, very high blood pressure in a young individual with manifestations of neurofibromatosis would lead one to suspect pheochromocytoma and therefore adjust therapy accordingly. Catecholamines secreted by these tumors, particularly norepinephrine, can cause myocardial injury by a multitude of mechanisms. Extra-adrenal pheochromocytomas are invariably norepinephrine secreting. Norepinephrine decreases coronary blood flow by vasoconstriction and concurrently increases myocardial oxygen consumption by causing hypercontractile tachycardic myocardium. This can result in myocardial ischemia.⁵ Furthermore animal and human models have clearly demonstrated that persistent, prolonged and intense vasospasm can cause endothelial injury, the end result of which is platelet aggregation, activation of the coagulation system and thrombus formation. The myocardial stunning-like phenomenon during a pheochromocytoma crisis has been reported. It is thought to be mediated by direct catecholamine induced toxic effect on myocytes, as well as due to diffuse coronary vasospasm and tachycardia, resulting in myocardial oxygen supply that does not meet demand.^6,7 In isolated cases reported in literature either one of these mechanisms could be the predominating feature resulting in a clinical presentation of cardiomyopathy and pulmonary edema or an acute myocardial infarction with characteristic ECG changes.^8,9 The hallmarks of pheochromocytoma-induced cardiomyopathy are segmental wall motion abnormalities that need not fit a distribution of the coronary arteries, and frequently, reversibility of cardiac dysfunction.¹⁰ Treatment of acute myocardial infarction in the presence of a pheochromocytoma requires a unique approach. As mentioned, the pathogenesis of pheochromocytoma-induced myocardial infarction is likely multifactorial and can vary among patients. The adrenergic effects of catecholamines increase myocardial oxygen consumption, promote vasoconstriction of diseased coronary segments, enhance platelet aggregation and increase shear stress upon pre-existent plaques, which may have otherwise been stable. Therefore use of antithrombotic agents such as heparin, aspirin and clopidogrel should be as useful as with more traditional myocardial infarctions. As far as reperfusion therapy however, caution should be exercised in the use of thrombolytics in these patients. The concurrent labile hypertension or hypertensive crises often seen during the presentation of acute myocardial infarction will increase the risks of their use. Consequently, reperfusion therapy with primary percutaneous intervention becomes not only an attractive alternative, but frequently the only available modality. Anti-ischemic therapy with use of beta-blockers is also controversial in these patients due to the adverse effects of unopposed beta blockade. Coronary vasospasm induced by catecholamine stimulation of coronary arterial alpha-receptors may be worsened without the compensatory vasodilatory effects of beta receptors on the coronary vessels. The initial administration of intravenous metoprolol in this patient had an adverse effect not only on systolic blood pressure but also on signs of ischemia as manifested by the presence of chest pain and ECG changes. The use of calcium channel blockers in the traditional setting of an acute coronary syndrome has been discouraged. Given the prominent role of vasospasm in the pathogenesis of acute myocardial injury and subsequent myocarditis and cardiomyopathy in this subgroup of patients however, use of calcium channel blockers alone or in combination with nitrates appears to be an attractive alternative. Summary. This case demonstrates the need to maintain a high index of suspicion for pheochromocytoma in patients presenting with labile hypertension, ischemic changes on ECG and reversible left ventricular dysfunction by echocardiography. In addition, early diagnosis of pheochromocytoma is imperative in patients presenting with acute myocardial injury. Unlike traditional cases of myocardial injury, unopposed beta blockade in these patients may potentiate the ischemic cascade as outlined above. Modification of traditional treatment approaches to both myocardial infarction and pheochromocytoma is required when both conditions occur simultaneously.

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