Elsevier

Cardiovascular Pathology

Volume 21, Issue 4, July–August 2012, Pages 334-338
Cardiovascular Pathology

Original Article
Segmental arterial mediolysis—an iatrogenic vascular disorder induced by ractopamine

https://doi.org/10.1016/j.carpath.2011.09.003Get rights and content

Abstract

Background

Segmental arterial mediolysis, an uncommon arterial disorder most often occurring in the splanchnic muscular arteries of the abdomen, is a cause of catastrophic hemorrhages. Its histology and initial clinical presentations suggested that it represented a localized norepinephrine-induced vasospastic response to perturbations in vascular tone and blood volume distribution caused by coexisting vasoconstrictor conditions. However, later presentations were at odds with some aspects of this hypothesis.

Methods

Nine greyhound dogs were administered a single dose of ractopamine. Two dogs developing persistent conduction abnormalities with biochemical evidence of heart injury were euthanized and necropsied—one 4 days and the other 17 days after dosage This report is based on findings and comparisons of the canine abdominal and coronary arteries to segmental arterial mediolysis.

Results

Lesions having features of early-injurious-stage segmental arterial mediolysis were identified in the canine arteries 4 days postractopamine, and arteries examined after 17 days showed alterations typically occurring in reparative-stage segmental arterial mediolysis. It is suspected that ractopamine, a Beta-2 adrenergic agonist, created segmental arterial mediolysis by neuromodulating the peripheral sympathetic nervous system to release norepinephrine from varicosities of efferent nerves serving splanchnic arteries that stimulate alpha-1 receptors to induce injury at the adventitial medial junction and medial muscle apoptosis.

Conclusion

This finding and other cited examples suggest that segmental arterial mediolysis may be a disorder principally caused by iatrogenic or accidental exposure to alpha-1 adrenergic receptor agonists or Beta-2 agonists able to release norepinephrine from the peripheral nervous system.

Introduction

Segmental arterial mediolysis (SAM), an uncommon nonsystemic disease occurring at all ages, most often presents with sudden catastrophic hemorrhages in the abdominal cavity, in the retroperitoneum, or at the base of the brain. It is a disease of the muscular arteries in these locations and in the heart. The bleeding is caused by ruptured aneurysms fashioned from arterial gaps created by mediolysis and intimal loss and/or arterial dissections produced at the gap outer medial muscle interface or from granulation tissue formed as a reparative response to the tearing separation of the outer media from the adventitia [1], [2], [3], [4], [5].

SAM does not appear to be atherosclerotic, infectious, immunological, or congenital in origin. Slavin and coworkers have proposed that SAM represents a vasospastic disorder principally caused by norepinephrine [3], [4].

Recently, Yaeger et al. [6], in a study designed to detect the metabolites of ractopamine, a Beta-2 agonist in the urine of greyhounds, discovered a vascular lesion similar to SAM in renal, hepatic, and coronary arteries in dogs necropsied because they developed severe cardiac conduction irregularities with heart failure following the administration of this drug.

This article will describe the canine arterial lesion, compare it to SAM, and develop a hypothesis that implicates this and similarly acting drugs in the genesis of SAM.

Section snippets

Methods and materials

Nine greyhounds were administered ractopamine to investigate the ability to detect this compound and its metabolites in urine by a pari-mutuel testing laboratory. Each dog was given a single dose of 1 mg/kg of ractopamine orally.

Seven of nine dogs developed pronounced cardiac arrhythmias and had elevated troponin I levels. Rhythm abnormalities resolved in all but two dogs, one euthanized and necropsied 4 days postdosing and the second euthanized and necropsied 17 days after ractopamine

Arterial

The dog sacrificed 4 days following the administration of the ractopamine protocol exhibited lesions in the distal renal arteries and their hilar branches, large intrahepatic arteries and extramural coronary arteries and their large perforating branches. The arteries of the intestinal tract and brain were not examined. The pathologic alterations in all the involved arteries centered on the adventitial–medial junction where linear fibrin deposition and smooth muscle necrosis occurred. The fibrin

Discussion

Initial reports of cases of SAM indicated that SAM frequently arose in elderly patients with a background of one or more disorders associated with vasoconstriction [3]. This finding coupled with the SAM's morphologic characteristics—segmental distribution, resemblance to the fibrinoid necrolysis of malignant hypertension, vacuolar muscle alterations, and minimal reactive inflammatory changes—led Slavin and coworkers [2], [3], [4] to suspect that vasospasm was the cause of SAM. It was

Acknowledgments

The authors would like to thank John Levin for his invaluable help with the digital photography.

References (13)

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    Bleeding in the injurious phase occurs from gap junctions and in the reparative phase it occurs from fragile vessels of the granulation tissue between the outer media and adventitia [5,13]. Stenosis in the injurious phase is due to thrombus formation and overgrowth of the granulation tissue and plaques in the reparative phase [5,11,13]. Differential diagnosis of the renal infarcts and dissection include congenital conditions (Ehlers-Danlos, Marfan, Loeys-Dietz), vasculitis (Behçet disease, polyarteritis nodosa, neurofibromatosis), embolism, coagulation disorders, renal trauma (iatrogenic), infection (mycotic aneurysm and endocarditis), aortic dissection, atherosclerosis, FMD, and SAM [15].

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    First, a causative relationship between SAM and β2 agonist administration has been established through animal experiments. Slavin and Yaeger have demonstrated that the oral administration of a single dose of ractopamine, a β2-adrenergic agonist drug, induced SAM in greyhound dogs.4 Indeed, characteristic arterial lesions of the early injurious stage of SAM were observed 4 days after the administration of the β2 agonist, as were typical alterations of the reparative stage of SAM 17 days later.

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