Segmental arterial mediolysis (SAM), an uncommon arteriopathy putatively caused by norepinephrine released by alpha-1 adrenergic agonists or some Beta-2 agonists capable of releasing norepinephrine from the peripheral sympathetic nervous system potentially can present ischemic and organ injury symptoms caused by sequelae created in its reparative phase in lieu of catastrophic hemorrhages announced in its injurious phase. The case documents this presentation—the patient presenting renal infarcts and ischemic lesions causing abdominal angina, hypertension and a nephrectomy event developing 10 years after prolonged ritodrine treatment for premature labor. This agent may have directly caused SAM or sensitized the patient to agonists causing SAM encountered at a latter date. A variety of lesions derived from injurious phase arterial injuries characterize reparative phase SAM. All were encountered in a hilar branch of the resected renal artery. These included side-by-side sequela aneurysms grossly forming a large fusiform aneurysm, granulation tissue filling adventitial medial tear spaces in which a dissecting hematomas developed, medial muscle loss centered to the outer media repaired with fibrous tissue, arterial stenosis created by reparative intimal plaques, and arterial thrombo-embolism. These lesions were mirrored in accompanying radiologic studies. The accompanying renal vein exhibited changes consistent with repair of the spastic venous angiopathy that often accompanies abdominal SAM. This angiopathy, putatively induced by Endothelin-1, suggested that this agent played a role in the genesis of the arterial lesions. Angiographic resolution of non-treated sequelae occurred in 5 months either spontaneously or due to treatment with bosentem. Conclusions: The histologic and angiographic changes demonstrate that the clinical onset of reparative SAM may be significantly delayed to produce ischemic lesions, renal infarction and in this case report, medial fibromuscular dysplasia in the hilar branch of the renal artery.
Catastrophic hemorrhage occurring in the abdominal cavity and/or at the brain base is the most striking and recognized symptom announcing segmental arterial mediolysis (SAM), an uncommon potentially lethal arteriopathy believed to be principally caused by an iatrogenic or accidental exposure to alpha-1 adrenergic receptor agonists or to B-2 agonists able to release norepinephrine from the peripheral nervous system [1,2]. On the basis of histological and radiologic studies that reported nonsymptomatic lesions in the injurious phase of SAM, it was postulated that SAM might also present in another fashion—as an ischemic disorder alone or associated with organ injury created by sequelae stemming from these non-symptomatic injurious lesions [
The patient, a female physician, pregnant at age of 38, developed premature labor in her 19th week of pregnancy. She was treated for this with the tocolytic agent ritodrine for the following 17 weeks. The ritodrine was administered at a dosage of 10 mg every 4 hours except for a 20-day period of intravenous dosage starting in the 26 weeks of pregnancy. The total IV dosage is unknown. During treatment with ritodrine she exhibited bouts of tachycardia, flushing and tremor. Her delivery was uncomplicated and the delivered infant boy did not exhibit any detectable abnormalities.
Ten years after delivery, the patient suddenly developed severe pain in the left lumbar fossa radiating to the abdomen lasting for about 36 hours. This was initially attributed to renal colic. Six days later the pain recurred and was now localized to the epigastric and mesogastric regions. This prompted hospital admission. The pain improved with bowel rest, analgesics and treatment with omeprazole. Laboratory blood tests revealed a moderate elevation in Lactate dehydrogenase and hematuria. Radiological studies were performed 11 and 21 days after the onset of symptoms. These showed a left renal infarct and the vascular abnormalities illustrated and described in Figures 1 to 5. On the bases of the laboratory findings and the renal radiologic studies a diagnosis a left renal infarct was established and a diagnosis of SAM was made supported by the intestinal angiographic findings.
The day following the first radiologic study, the patient was readmitted to hospital because of the recurrence of severe abdominal pain. This was attributed to recurring renal infarcts from emboli from the lobar branch of the left renal artery and was treated with catheterizing and an attempted placement of stents in the left upper renal artery together with fibrinolysis. Unfortunately successful endoluminal treatment by the vascular surgeons could not be accomplished and the placement of the stent in a subintimal position caused a dissection. The worsening of symptoms and the elevation of her blood pressure provoked a left nephrectomy that was performed 39
days after the onset of symptoms. Three weeks post nephrectomy abdominal pain recurred caused by a right renal infarct. This was small without any impact on renal function or blood pressure and for these reasons intervention was not attempted. She was treated with oral anticoagulants. The patient continued to have episodes of abdominal pain treated with analgesics, suspected as representing abdominal angina. A year later the patient was placed on a Bosentan regimen and she states that her symptoms have since improved and her blood pressure is no longer elevated. Cardiac studies performed on the patient revealed no abnormalities. Five months after her bosentem was initiated repeat angiographic studies showed resolution of remaining arterial sequelae (Figures 6 and 7) and the return of well being in the patient except for the occasional occurrence of minor episodes of abdominal pain.
MorphologySections of the kidney show a focal organizing infarct. An adjacent interlobular artery contains an organizing
thrombo-embolus and a recent embolus is evident in a hilar artery. The arterioles do not show hypertensive changes and no other renal abnormalities are evident.
The hilar branch of the renal artery exhibits two sideby side aneurysms whose walls are stoutly reinforced by mature granulation tissue that in one has focally extended over the contiguous artery wall to form an intimal plaque (
shows patchy linear loss with fibrous tissue replacement that focally extends into the mid-media (
Focal areas of acute hemorrhage are evident in granulation tissue developed between the outer media and adventitia (
The adjoining renal vein displays areas of luxuriant fibrosis of the outer media that separates and replaces smooth muscle bundles widening the vein (
A thin elastic fiber containing plaque incompletely overlies the intima.
SAM is a biphasic clinical disease. Its most recognized presentation is striking and potentially catastrophic abdominal hemorrhages. This principally develops without sexual preference in late middle-aged or elderly patients and is caused by ruptured gap-aneurysms [
changes that weaken the muscle-stromal connections thereby facilitating medial island separation, a heightened sensitivity to sympathomimetic agonists and the usage of these agents to combat cardiogenic and septic shock conditions not infrequent in the elderly. However, other arterial lesions occur alone or concurrently with gap aneurysms. These are areas of mediolysis of lesser intensity with preserved intima and foci of adventitial-medial separation putatively induced by violent medial muscle contraction and/or an apoptotic induced tear at this site. These two lesser injuries and small gaps may be initially asymptomatic due to the rapidly forming reparative granulation tissue that evolves as a response to the injurious lesions, and initiates the second reparative phase of SAM [1,3,4]. This vigorous reparative response and the absence of gap-aneurysms accounts for the paucity of clinical reports of injurious phase abdominal SAM in young adults. These asymptomatic lesions may resolve, persist or develop into sequelae that cause ischemic lesions and organ injury [
Sequelae are created in both the adventitial-medial junction tear site and in the media. In the former location the small vessel component of the reparative granulation tissue bleed to cause mural hematomas or dissecting hematomas. These can originate immediately following the injurious phase or their development may be delayed weeks, months and even years after the initial onset of SAM [3,5]. Medial sequelae develop from repaired arterial gaps whose lumens may be narrowed by intimal plaques created by the expansion of medial granulation tissue over the adjacent intact intima and by aneurysm walls amply buttressed by granulation tissue. Concurrent thrombi cause further luminal narrowing or luminal occlusions. The granulation tissue that reinforces arterial aneurysms prevents rupture with bleeding but extensive abdominal hemorrhage from sequela aneurysms can occur-an exception to the ischemic axiom of reparative phase SAM. Finally sequelae may generate fibromuscular dysplasia (FMD), the type dependent upon the principal location of the reparative granulation tissue in the artery [
The histological and angiographic findings and clinical symptoms in the current case are a classic representation of reparative phase SAM converted to FMD. An assortment of arterial lesions detected both histologically and radiologically is an important diagnostic feature of both injurious and reparative phase SAM. This variety is created by the varying intensities of the two different arterial injurious lesions, their asynchronous maturation, degree and sites of florid repair and segmental distribution [
Organ injury is under appreciated initial manifestation of SAM. It may present in the injurious or reparative phases of SAM alone or accompanied by other arterial lesions as in the present case. In addition to renal infarcts [
Judging from the fibrosis of the reparative alterations visualized in the outer media we suspect that this lesion was of some duration. Since there was no history of abdominal hemorrhage, the injurious phase of SAM was apparently subclinical and may have dated back ten years to her prolonged treatment with ritodrine. This Beta-2 tocolytic agonist, pharmacologically similar to feneterol may also neuromodulate the peripheral sympathetic nervous system to synthesis and release norepinephrine [
The renal vein fibrotic lesion, consistent with the repair of an endothelin-1 (ET-1) induced venous angiopathy, suggests ET-1 may have potentiated the pressor activity of norepinephrine [1,4]. This lesion frequently accompanies abdominal SAM. ET-1, synthesized in capillaries in the adventitia of the adjacent abdominal arteries, cross-talking with the norepinephrine produced in the ganglia of the efferent sympathetic nerve endings in the outer arterial wall potentially can convert a norepinephrine induced vasoconstrictor physiological stimulus into SAM [
This case illustrates how SAM, presenting in a premenopausal female exposed to Beta-2 tocolytic agonists capable of causing the release of norepinephrine, can be transformed into clinical FMD by transiting a subclinical injurious phase before its reparative sequelae initiates the renal infarction and ischemic bowel symptoms that clinically announced this entity.
The principal author wishes to thank and express his appreciation to Dr. Teresa Lozano for her help in gathering and forwarding to me the clinical, radiological and histologic data for this article and to Jeffery Forsyth for his invaluable help with computer problems and Jason Slavin for his assistance in formatting the digital images. No funding agent played a role in the preparation or writing of this manuscript.
Authors have declared that no competing Interests exist.
First author wrote the first draft of the manuscript, photographed the pathologic changes and assembled the references, the second author contributed the radiological findings and descriptions, the third, forth and sixth authors managed the clinical aspects of this manuscript and the fifth author supplied the pathologic material for this study. All authors have read and approved the final manuscript.
The patient has consented to be presented in this manuscript and indeed is one of its co-authors.