Morphologic characteristics and functional significance of focal fibromuscular dysplasia of small coronary arteries

Morphologic Characteristics and Functional Significance of Focal Fibromuscular Dysplasia of Small Coronary Arteries Thomas N. James, MD

Focal fibromuscuiar dysplasia of small coronary arteries is not so rare as it is unrecognized. Although sometimes occurring as an isolated abnormallty, it more often accompanies a variety of other lesions including inflammation or infiltration. In this review based on personal study of over 1,OCO human hearts, the 3 topics imkuie a description of the morphologic characteristics of the lesion, a discussion of its functional consequences affecting coronary flow, and an iteration of theoretical explanations for its development. The typical lesion is focal in distribution, is comprised of both fibrous and smooth muscle elements, and the histdogic organization is one of dysplastic array. lnekuled among the subjects discussed in functional consequences are coronary spasm, coronary reserve, chest pain, electrical instability of the heart, and comments on the role of focal fibromuscular dysplasia of small coronary arteries in hypertension, myocardial hypertrophy and heart failure. Theories as to its development include primary faults of smooth muscle or collagen, and focal abnormalities of clotting or neurovascular relation, but it is likely that the cause is multifactorial. (AmJCardiol1990;65:126-226)

From the World Health Organization Cardiovascular Center and the Department of Medicine and the Department of Pathology, University of Texas Medical Branch, Galveston, Texas. This work was supported in part by the Pegasus Fund of the University of Texas Medical Branch, Galveston, Texas. Address for reprints: Thomas N. James, MD, University of Texas Medical Branch, Galveston, Texas 77550-2774.

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ocal fibromuscular dysplasia is probably best known in relation to the narrowing of 1 or both renal arteries-3 which often produces hypertension. But with growing attention to the more precise definition of arterial lesions it is now apparent that the same abnormality may also occur in the carotid,4-6 mesenteric,’ iliac8 coronarygel l and other arteries in the body. It appears likely that focal fibromuscular dysplasia will eventually be recognized in virtually every vascular bed.‘2-i4 For some years there has been increasing awareness of the clinical significance of functional and morphologic abnormalities of the small arteries of the heart.‘5-57 In my own studies,58-94it has become apparent that focal libromuscular dysplasia is one of the more frequently encountered histologic abnormalities, and that some diseases are particularly associated with it. The 3 purposes of this review are to describe the histologic features and variable prevalence of focal fibromuscular dysplasia of small coronary arteries in several different illustrative diseases, to discuss the functional significance of these lesions, and to offer some hypotheses as to the development of this abnormality. METHODS

During the past 30 years I have dissected and examined histologically over 1,000 human hearts, primarily from cases of sudden unexpected death or from patients dying with diseases having distinct morphologic characteristics such as amyloidosis, hemachromatosis or various forms of arteritis. One consistent goal of those examinations has been the clinicopathologic correlation between findings in all elements of the conduction system of the heart and the clinical occurrence of arrhythmia, conduction disturbances or sudden unexpected death. Details of the methods used have been reported.95,96 Because the sinus node artery and the atrioventricular (AV) node artery are both small, and because each of these is routinely sectioned at no more than 2-mm intervals, and are always examined in every heart, there is a unique opportunity to assesstheir structure fully and to compare the findings among a large number of different human hearts. Furthermore, the routine sections prepared for study of the sinus node always include several centimeters of adjacent atria1 wall, while the routine sections to examine the AV node and His bundle always include several adjacent centimeters of both the interatrial and interventricular septa. For routine frontal plane

TABLE

I Clinical

Age W

and

Pathologic

Features

of Nine

Cases

Usual BP (mm W

& Sex

of Essential

Cause

Hypertension* Hrstopathology of Small Coronary Arteries

of Death

Dissecting aorta Carcinoma,

aneurysm,

58, white

man

180/120

71. white

man

180/100

72. white

man

220/100

68, white

man

160/100

Congestive failure & pneumonia Acute Ml and rupt. IVS

58, black

woman

284/184.302/180

Cerebrovascular

73, white

man

200/100

Acute

49. white

man

270/130

64, white

man

200/140

Congestive thromb. artery Congestive

65, white

man

210/110

Acute

FFMD 4+, AVNA; all other small aa. unremarkable FFMD AVNA and SNA, l+; scattered fibnnoid necrosis. No other abnormalities small aa FFMD 2-3+ AVNA and SNA plus atrial aa.; ventricular aa. unremarkable FFMD AVNA 4+; FFMD SNA and IVS aa. l+; other small aa. unremarkable FFMD SNA and RA aa., 4+; FFMD AVNA 2+; FFMD IAS & IVS aa.. l+; scattered fibrinoid necrosis Medial fibrosis IVS aa. & AVNA. 2+; other aa. unremarkable Old recanalizing thromb. SNA; FFMD SNA & RA aa. If; FFMD AVNA 2+; IVS & IAS aa. unremarkable Minor medial fibrosis, SNA; other arteries unremarkable FFMD AVNA 2+; all other aa. unremarkable

prostate

accident

Ml failure & mesenteric failure

Ml and rupt.

* Archwal cases from 1955 to 1965 (before most currently available therapy). aa. = arteries; AVNA = atrwentncular node artery; BP = blood pressure: FFMD = focal fibromuscular dla ([ l+] to more than 90% narrowing of the lumen [4+]); IAS = interatrial septum; IVS = lnterventricular = sinus node artery: thromb. = thrombosis.

sections, the tissue of the interventricular septum always contains transverse cuts through multiple long septal branches of the left anterior descending artery, as well as the smaller number of the posterior descending artery’s shorter septal branches. 97 Thus, there is an abundant sampling of both atria1 and ventricular small coronary arteries, defined arbitrarily as those with external diameters of 0.1 to 1.Omm. In most cases,additional samples of myocardium from the free walls of right and left ventricles are also examined. For the purposes of the present report, I examined the hearts of 9 patients who died with essential hypertension, the terminal event usually being congestive heart failure or a cerebrovascular accident or myocardial infarction. These 9 cases (Table I) were selected from archival files on the basis of hypertension being the principal clinical problem during life. All cases with diabetes mellitus, or with any systemic arterial diseases such as polyarteritis nodosa, rheumatic heart disease or syphilis were excluded. For comparative purposes, 1 case of coarctation of the aorta98 and 3 cases of pheochromocytomas6 were reexamined. MORPHOLOGIC CHARACTERISTICS OF FOCAL FIBROMUSCULAR DYSPLASIA OF SMALL CORONARY ARTERIES Definition: All 3 words are important for an accurate understanding of focal fibromuscular dysplasia. First, the abnormality is typically focal and rarely extends more than a few millimeters along the course of an artery. In small arteries it may be considerably less than 1 millimeter in length but even then can cause marked reduction in luminal diameter at that point. Second, the elements of the lesion include both fibrous and muscular components, a mixture of collagen, tibroblasts and smooth muscle cells

IVS dysplasia septum;

grading of FFMD ranged from mnmal thtckening of the tunIca me. Ml = myocardial Infarction: RA = right atrlal; rupt. = ruptured; SNA

with variable irregular segments of elastic fibers. The typical lesion is often entirely within the tunica media and lies between relatively normal internal and external elastic laminae, but frequent variations include a partial or even predominant component of myointimal proliferation. Third, the histologic organization of the lesion is so disorderly that it is best considered as a dysplastic process. The typical lesion: The usual dysplastic thickened tunica media lies between relatively normal internal and external elastic laminae (Fig. 1). But in many casesthere is an additional or even predominant component of myaintimal dysplastic thickening (Fig. 2). There is no inflammation within or around the artery, although fibromuscular dysplasia is sometimes a late sequella of arteritis. The endothelium at foci of fibromuscular dysplasia is usually intact and thus not conducive to local thrombosis; however, in special cases mutiple foci of microthrombi may be associated with libromuscular dysplasia78 as discussed later. There are no distinctive local neural lesions in association with focal fibromuscular dysplasia, but this should not be interpreted as precluding the possibility of abnormal neural function locally. Most lesions are only 1 or a few millimeters in length, yet any one of them could, of course, obstruct flow into the entire downstream segment of the artery, the remaining wall and lumen of which may be completely normal. In some diseases many profiles of small arteries seen in histologic sections exhibit focal tibromuscular dysplasia, with this being virtually the only histologic abnormality of small coronary arteries.64~71~79~82*83 In other diseases,58-60,6568,78,84,86,87,89,91,92 focal fibromuscular dysplasia is only one of a variety of arterial abnormalities, with some other lesions including arteritis, mural infiltration (e.g., amyloid), thrombosis and intimal proliferation.

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underestimate both the extent and significance of such lesions unless one keeps in mind a 3-dimensional image of the problem.

conceptualiition:

One approach to quantify the extent of lesions in small coronary disease is to examine a certain number of arteries (e.g., 100) encountered consecutively in a histologic slide. However, with this approach which is popularly used, one is not examining arteries, per se, but only thin sections of arteries. In the human heart, small coronary arteries are often 20 to 30 mm in length and some special ones such as the sinus node artery may be as much as 100 mm long. Since the conventional histologic section is less than 10 P thick, it would require over 10,000 serial sections to evaluate fully even one of the longer small coronary arteries. Furthermore, because a local obstruction by focal fibromuscular dysplasia may be as small as 1 mm in length but the lumen severely narrow at that point, finding such lesions is not easy. Thus, the presence of 5 or 10% of luminal narrowing of lesions found in thin histologic sections by examining exclusively 2-dimensional profiles of small coronary arteries will virtually always 146

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FIGURE 2. Photsmicrographs of the atriovenbidar nods artery from a young man dying with cardiomyopathy of progresslve muscular dystrophy. Stain in A is Verhoeff-van Gleson elasttc, dsmonstratlng that vlrtuaEy 1 the ttbromuscular dysplasia is of a myointimal typs. B shows v medial &generatlon (3 open arrows) in branches of the atrioventricular nods artery. (Reproduced with pernlm from circula-

FIGURE 1. Focal fibromuscular dysplasia of ths sinus nods artsryisshownhsrefrsmtheheartofayoungatktewho dledsud&dy.AadBarephotomk8qgr~fromadjaced wcttons,withthsstahinBbeingVehosff-vanGiielastic illustrations being ths and the one in A and all saheqmd thhromeunlessohtwiiinbcaed. Allofthl?fikofizi!z dysplasiahsreisconthedbetwsenthsintsmaland extemalelasticlaminae,thusrepre=dngthetMcamsda.A danwxmtofintimalproliiat&nisadditionallyseeninB. Allmagnificationrindicatedwith -bars.

Importance

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FUNCTIONAL SIGNIFICANCE OF FOCAL FIBROMUSCULAR DYSPLASIA OF SMALL CORONARY ARTERIES

Spasm of small coronary arteries: Although it was long debated whether large coronary arteries often exhibited functionally important spasm (now generally conceded to be a frequent clinical problem), it has always been recognized that the small arteries act as modulators of coronary flow by varying their luminal diameter in response to either neural or humoral influences. There is evidence that some substances such as neuropeptide Y may selectively constrict small coronary arteries,gg whereas dipyridamole61 and uridine triphosphate75 may selectively dilate them, i.e., independent of the constricting or dilating effect on large epicardial coronary arteries. More relevant to the present discussion, there are special considerations to be made in regard to focal tibromuscular dysplasia. First, the tunica media in focal fibromuscular dysplasia is histologically not well organized,

but simply by its mass may narrow the lumen of the vessel. This tunica media is unlikely to permit dilation in response to agents of reactive hyperemia or other circumstances of metabolic need. Second, in an artery with a thickened tunica media, any constriction at all has an enormously greater narrowing effect than in an artery with tunica media of normal thickness. For example, as little as 17% decrease in the external (overall) radius by spasm of a small artery narrowed 30% by medial thickening will cause an 80’% decrease in the internal (luminal) radius. For a small artery with 50% narrowing of the lumen by medial thickening, a mere 9% decrease of the external radius by spasm will completely occlude the 1umeC’ (Fig. 3). Longitudinal propagafh of contraction: It has recently been demonstrated by Araki et allo that smooth propagation of contraction develops in epicardial coronary arteries of both human and porcine hearts and that the propagation may depend on calcium influx. If this is also true for small arteries, where active vasomotion has been the subject of extensive investigation,18,20,26,44-47J02lo5 then the functional significance of focal fibroniuscular dysplasia or any focal small arterial lesion acquires a different and fascinating dimension. For example, progress of flow within a small artery where active propagation of mural contraction was impeded may be altered in important ways simply because vasomotion was deranged. Eddy currents, distorted streamlining and vascular stasis are all possibilities. Hydraulic engineers have demonstrated with in vitro studies that the linear flow of non-Newtonian fluid within tubes may be completely obstructed or even reversed by experimentally produced local turbulence caused by strategically placed baffles even though there was still a patent lumen of the tube.lo6 Analogous turbulence of flow may well be produced by focal fibromuscular dysplasia, both by direct partial luminal obstruction and by altered longitudinal propagation of contraction.

FFECT OF MURAL

NORMAL

THlCKENiNG

ON CONSTRICTIVE

DISTENDED ARTERY R. R, = 1 2

NARROWIN(

NORMAL CONSTRICTED ARTERY 25% DECREASE IN R. 39% DECREASE IN R,

ARTERY WITH 30% LUMINAL STENOSIS

ARTERY CONSTRICTED 17% DECREASE IN R. 80% DECREASE IN R,

ARTERY WITH 50% LUMINAL STENOSIS

ARTERY CONSTRICTED 9% DECREASE IN R. 100% DECREASE IN R,

FlGURE3.7ltemagnifkdeffectofvasocoMWhhart~ with thickened wab. See texl far disadon. us;%=outsideradius.(Regmducd[withdightmodiRdh] wiul pemlissiml from Ci~th?n.‘oq

Ri=inMeradi-

How often that is partially or entirely secondary to a prior inflammatory lesion is unknown. In some hearts there are isolated lesions of the sinus node artery63,71,85or the AV node artery79 without much involvement of small coronary arteries elsewhere in the heart. The functional significance of such lesions resides in their influence on the electrical stability of the Variabk prevalence of focal fibromuscuk dysplaheart.77J07-109Why these particular sites should be subject to focal fibromuscular dysplasia will be discussed sia: In some diseases such as scleroderma82 or idiopathic cardiomyopathy,23*31,64,83,94focal fibromuscular dyspla- later in considering the possible pathogenesis of focal sia may be the only or certainly the predominant abnor- fibromuscular dysplasia. mality of small coronary arteries (Fig. 4 and 5). Even in !specm small coronary arteries involved by focal fisuch diseases, both the number of narrowing lesions and bromuscular dysplasia. When the blood supply to the their distribution vary greatly. In other diseases such as conduction system of the heart is impaired, as indicated in progressive muscular dystrophy5* or Friedreich’s ataxia the preceding section, one may expect disturbances of with cardiomyopathy,60,92 or primary pulmonary hyper- impulse formation, acceleration or deceleration of the tension with small coronary disease,59 there is a wide rate of the cardiac rhythm or genesis of arrhythmias, and variety of different arterial lesions, including medial de- impairment of conduction, with the ultimate electrical generation with or without medial hemorrhage, intimal instability being represented by sudden death. Two other proliferation, or medial infiltration with an unidentified general groups of small coronary arteries are those supSchiff-positive material; however, in the same hearts and plying the working myocardium throughout the heart, sometimes even at different sites in the same artery one and all of the coronary anastomoses. Unlike the small may also find focal fibromuscular dysplasia. None of the arteries supplying the conduction system, there are so preceding examples exhibit any form of arteritis except many small arteries distributed to the working myocardivery rarely, but there are forms of cardiomyopathy asso- urn that narrowing lesions in one or a few of them may be ciated with both infectious arteritis as in Whipple’s dis- of little functional significance. Unfortunately, it is that ease,84*91or noninfectious arteritis such as occurs in poly- fact which has mistakenly led some investigators to conarteritis ncdosa67 or rheumatoid arthritis,87 in which fo- sider that narrowing lesions in any small coronary artery cal fibromuscular dysplasia is also abundantly found. may be ignored. THE AMERICAN

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FfGURf! 4. Focal ffkomurcular +Spk3riehShOWnhweh acaseoffatddsmdemm heartdisease.Thesman~ inA~fromthekftventricularmyocanHumandtheonein6 isfheafrbvebiahrnodecvtary.(Rywoduced sion from Chwlafioa.~

-CARDIAC

with

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FfGURE 5. These 2 examples of focal fibmmusah dysplasia arainarmallartwyottheintanantricularreptum(A)and oneinfheabiovedridarnoda(6jofamandyingwifhkPopathk cardiomyopathy of the asymmebfc type. (Reprodud with permission from Chwlafion.BJ)

For the sinus node artery, focal fibromuscular dysplasia may cause a special problem which is possibly related to the unusual incidence of this lesion in the sinus node of some victims of sudden death.32,63,71,85There is evidence to suggest that impulse formation by the sinus node is coupled with pulsation of the sinus node artery, thus forming a positive feedback system in which the generation of each sinus beat is normally influenced by a pulse in the sinus node artery.77J lo While sinus rhythm can clearly exist without such a pulse and is even demonstrable in vitro, regular cyclic pulsation in the sinus node artery may serve as an important stabilizing mechanism under normal circumstances. If this is so and sufficient focal fibromuscular dysplasia is present to dampen or eliminate the normal pulse in the sinus node artery, then an important stabilizing mechanism could be lost and electrical instability may be the result. For both the working myocardium’s small arteries and for those that comprise the coronary anastomoses, it is the total number and distribution of focal fibromuscular dysplastic lesions that become significant. When there are many such lesions in the working myocardium, the result is multiple foci of ischemic degeneration followed by focal fibrosis and compensatory hypertrophy of remaining myocardium. When there are many lesions among the coronary anastomoses, then collateral circula166

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tion is impaired. Unfortunately, hypertrophy and dysplasia of the tunica media of previously unstressed coronary anastomoses is a normal consequence of increased collateral flo~~~ and may paradoxically prevent the optimal development of the collateral circulation which they are functionally best designed to distribute.75 Diminished coronary reserve: There are now available several methods for evaluating the function of small coronary arteries by determining the “coronary reserve.” 25,29*36,46,47 In general terms, the methods measure total coronary blood flow before and after the administration of a vasodilator substance. Any lesion that impairs the ability of small arteries to dilate can be predicted to cause a diminution in coronary reserve. There are at least 2 ways in which focal fibromuscular dysplasia may influence the assessment of coronary reserve. First, if there is a sufficient number of such narrowing lesions, then either before or after the administration of a vasodilator one may expect coronary flow to be diminished compared with expected normal values. Second, whether coronary flow is not increased or is less than normally increased after a vasodilator has been administered will depend on whether the focal tibromuscular dysplastic narrowing lesions are still capable of permitting any dilatation or whether they have become so stiff as to have a fixed luminal diameter (or none at all).

Role in cheti pain: Patients with small coronary disease, including that due to focal fibromuscular dysplasia, often have chest pain that resembles angina pectoris in location and subjective description, although it it not regularly produced by emotional or physical stress and is not regularly relieved by usual measures. It has been suggestedssJ9,72J8 that the pain represents the chance concurrence or coalescence of several foci of myocardial ischemia produced by multiple small coronary narrowings either from simple progression of the disease or due to intermittent spasm. The usual electrocardiographic pattern is one of widespread persistent T-wave inversion. Transient arrhythmias, when arteries to the conduction system are involved, would contribute to episodic bouts of myocardial ischemia by making coronary perfusion generally diminished, and especially so in regions where focal fibromuscular dysplastic narrowing already existed. Role in suiuddendeath: The conduction system is not spared in any small coronary disease of which I am aware, although the involvement seems to be of random occurrence along with any other of the small coronary arteries. In addition to the effect on cardiac rhythm and conduction by focal fibromuscular dysplasia of arteries to the sinus or AV node, or both,63,71,79,85coexistence of similar lesions throughout the myocardium would introduce still further jeopardy by focal changes in excitability and conduction in the atria1 and ventricular working myocardium which could compound the hazard of lethal electrical instability of the heart. Role in hypertension: Coronary reserve is significantly diminished in patients with essential hypertension.39,46,47,111,112 For that reason, perhaps the most important lesson provided by the brief review of the hearts from patients dying with essential hypertension (Table I) is that all the lesions of small coronary arteries were focal. There was no generalized abnormality such as diffuse or lengthy segments of medial hypertrophy. Of the focal lesions found, tibromuscular dysplasia was the most prevalent. Most of the hearts exhibited fewer small coronary abnormalities than are usually encountered in other systemic diseases such as scleroderma or polyarteritis nodosa, even though it is probable that in each of the hypertensive casesthe internal arterial stress was sustained and of considerable magnitude. The total number of hearts studied was small (n = 9) and the level of hypertension varied and its constancy or periodicity was not specifically studied; however, there was not much difference among the hearts, and all arterial lesions were focal and the overall severity wasgenerally moderate. Except for numerous platelet aggregations and some endothelial proliferative lesions in pheochromocytoma,86 there was no remarkable difference in the small coronary arteries of essential hypertension, coarctation of the aorta and pheochromocytoma, all exhibiting some focal fibromuscular dysplasia. Variability of abnormalities (both prevalence and severity) in small arteries in the kidney and other organs, as well as those in the heart, remains one of the puzzles about essential hypertension, i.e., what determines focal susceptibility at one site in an artery and spares other sites.

It has been suggested that coronary artery disease in hypertension represents a conundrum. ’ 13 Muhiple lines of evidence either support or refute several preferred explanations for the recognized reduction in vasodilator capacity (coronary reserve), one of these being structural changes in the resistance vessels, i.e., small coronary arteries. My own findings, however, would support the editorial suggestion that structural changes in small coronary arteries may have been missed.‘13 Two reasons are the fact that such changes tend to be focal in nature (Table I) and that even a significant number of such lesions are difficult to find and usually is underestimated.92 Finally, the editorial suggestion that treating hypertension might be beneficial through regression of such lesions’ l3 is probably best supported by the fact that most lesions seem to be focal fibromuscular dysplasia; whether that suggestion proves to be true depends on a better understanding of the pathogenesis of focal fibromuscular dysplasia which will be discussed later. Role in hypertrophy: If focal fibromuscular dysplasia narrows the lumen of a small coronary artery sufficiently, and particularly if spasm is often superimposed, the expected effect downstream would be ischemia leading to focal necrosis and eventual fibrosis. When that myocardiurn is lost, its space or volume does not disappear but is replaced by scar, which itself occupies some space that may or may not equal in volume the amount of lost myocardium. Additionally, the remaining myocardium becomes more stressed and secondarily hypertrophies so that the eventual result of hypertrophy plus scar is an abnormally increased total cardiac mass and thickened myocardial walls. Rok in heart failure: If hypertension persists, the focal narrowing of small coronary arteries may be expected to continue, leading to progressive focal loss of myocardiurn with replacement fibrosis and compensatory hypertrophy, ending in an enlarged heart with more and more fibrosis and eventual decompensation and failure. This would apply not only to the small arteries responsible for direct nutrient circulation to the working myocardium but also to focal fibromuscular dysplastic narrowing of coronary anastomoses, thereby diminishing the only potential source of collateral circulation. If the arteries supplying the conduction system become involved in the process, arrhythmias and conduction disturbances would further impair the hemodynamic efficiency of the hypertrophied myocardium, thus adding multiple loops to the downward spiral of cardiac failure, with many different components of pathogenesis but with focal fibromuscular dysplasia of small coronary arteries as one prominent contributing factor. PATHOGENESIS OF FOCAL FIBROMUSCULAR DYSPLASJA OF SMALL CORONARY ARTERIES

There is no current explanation for this problem but there are several plausible theories to consider. As with so many questions in human biology, it may be predicted that there will not be a single explanation applicable to all cases,or even for all sites in the same heart, and in many THE AMERICAN

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there will be obvious multiple components to the pathogenetic mechanisms. The following theories are in no order of priority or probability. Leiomyomataid nodule: Recent studies concerned primarily with the development of atherosclerosis have focused attention on the tendency of smooth muscle in the tunica media of arteries to behave sometimes in a neoplastic or dysplastic manner.l14 What we see in small coronary arteries bears some resemblance to the histologic appearance of leiomyomata wherever found, but most of the arterial lesions are not eccentric or irregular in the way one would expect of a purely neoplastic lesion. Most examples of focal fibromuscular dysplasia are concentrically distributed, although the histologic organization is certainly dysplastic. What the stimulus may be for such changes to occur remains largely unknown, Compensation for weakness er degeneration, or both, of the tunica media: For large arteries one hypothe-

sis concerning the development of focal fibromuscular dysplasia cites mural ischemia, possibly caused by lesions in the vasa vasorum leading to reactive hyperplasia of both muscular and fibrous elements as is observed experimentally when the vasa vasorum are interrupted.13 In a similar manner it has been postulated that the luminalnarrowing disease in primary pulmonary hypertension may begin with medial atrophy or hypoplasia.115J16 The common denominator for such considerations may be functional weakening of the tunica media, which may even be a hereditary medial necrosis involving both systemic and pulmonary arteries, particularly those I1 mm in diameter. l l7 If one reasons that the normal role of the tunica media is to maintain optimal tone and to constrict as needed to control local coronary flow, then the loss of that regulatory ability would be undesirable. If the vessel cannot reduce its luminal diameter when required to do so, then teleologically one might anticipate some compensatory mechanism to reduce the lumen, and fibromuscular dysplastic narrowing would accomplish this. Of course, such an adjustment might be at the expense of a possible loss of dilating capability which is another regulatory mechanism, assuming that the artery with focal fibromuscular dysplasia is incapable of dilating. Actually, it is possible for increased pressure to distend an artery if the wall is not too rigid, but constriction is probably precluded if the tunica media is damaged or otherwise weakened. Thus, a fmed narrowing may be more acceptable relative to regulatory dynamics than would an uncontrollably dilated or distended small coronary artery. Generalized smooth muscle abnormality: In at least 2 diseases there are not only numerous foci of focal fibromuscular dysplasia of small coronary arteries, but also focal abnormalities of smooth muscle in the gastrointestinal tract (especially the lower esophagus) and other portions of the body.58,82J18-121For both scleroderma and progressive muscular dystrophy there is also reason to suspect neural abnormalities, particularly the Raynaud’s phenomenon often associated with scleroderma, which may secondarily influence smooth muscle wherever it is present, including both the heart and the esophagus. But 18G

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whether the fault lies primarily with the smooth muscle or is secondary to an abnormal neural influence on it, there may be a common denominator (as yet unidentified) for both the vascular and extravascular problems with smooth muscle. Genetic factors: It has been suggested that genetic factors may play a role in the development of focal fibromuscular dysplasia of large arteries13 on the basis of reported incidences within family groups.’ Furthermore, focal fibromuscular dysplasia of small arteries (in the kidney) has been described in patients with Alport’s syndrome which consists of hereditary deafness in association with nephritis. l** There may be a remarkably similar situation for the small coronary arteries of patients dying with the long QT syndrome associated with congenital deafness, where focal fibromuscular dysplasia of the sinus node artery has been observed.63~70However, victims of the long QT syndrome and sudden death, whether born deaf or hearing normally, also exhibit an impressive cardioneuropathy, 123bringing into consideration the possible importance of cardioneural disease relative to the development of the focal fibromuscular dysplasia, as will be discussed next. Fecal hyperactivity of sympathetic nerves: This theory would especially fit well with the apparent predilection of focal fibromuscular dysplasia for the sinus node artery and AV node artery, because both of these special arteries lie in regions with such rich autonomic innervation. It would also fit with the known hyperactivity of sympathetic nerves in diseases such as scleroderma and, of course, some cases of hypertension, and with the existence of focal fibromuscular dysplasia in the small coronary arteries of such cases. Another example includes idiopathic cardiac enlargement of the type usually diagnosed as cardiomyopathy, where the small arteries are now suspected in its development,23~31~64*83,94 but where an increased sensitivity to epinephrine and norepinephrine has also been an etiologic consideration. 124There is considerable evidence that norepinephrine can cause myocardial hypertrophy125 with or without hypertension. Whether the influence to hypertrophy also exists for smooth muscle of small arteries is less certain but seems logical. On the other hand, there are distinct examples of focal fibromuscular dysplasia of small coronary arteries without any myocardial hypertrophy, and without any other evidence of hyperactivity of the sympathetic nerves, such as hypertension, tachycardia, pallor, and so forth. Furthermore, if it is to be supposed that sympathetic hyperactivity is of a focal nature, then it will be necessary to explain the basis for whatever selectivity there is. Focal sympathetic denervation with hypersensitivity to circulating catecholamines: This is in some respects

the mirror image of the previous theory. For libromuscular dysplasia it might be simpler to expect focal denervation and local hypersensitivity to circulating catecholamines than to have isolated or focal hyperactivity by the sympathetic nervous system. In particular, focal denervation could explain the absence of more generalized evidence of sympathetic hyperactivity in most cases. For

FIGURE 6. Three dfhmmt deqkths offscal-dysplasiaaro dIown Mmnving sovoral smd artorks inthek#tveW+darmyocardlumota pakntWW-conganshl-Y* timaia.TwoopsiramwsinBmarkan anaorr#%lhyarof~ngphkwHhpetmidonfrwn

cases with coexisting myocardial hypertrophy and focal tibromuscular dysplasia of small coronary arteries one could postulate similar denervation supersensitivity for both the smooth muscle of tunica media and of cardiac myocytes. There is evidence of increased cardiovascular responsiveness to both epinephrine and norepinephrine not only in patients with hypertrophic cardiomyopathy,124 but also in patients with essential hypertension’ l 1 and with variant angina.126 At a more fundamental level the arterial “denervation” fault may be seen in terms of receptor activity or the cellular metabolism of smooth muscle in the tunica media. Any catecholamines present could be received with abnormal affinity, or their uptake and storage could be impaired, or their metabolic degradation could fail, and the net result would still be local sympathetic overactivity. For this theory, the question still remains: Why did the fault occur where it did, rather than in the entire artery or in many sites within it? Focal platelet aggregation: Platelet-derived growth factors are known to influence vessels as well as other tissues. 127-134 In pheochromocytomas6 and in congenital homocystinuria78 (Fig. 6), there is focal fibromuscular dysplasia of small coronary arteries as well as demonstrable widespread aggregation of platelets. However, in congenital homocystinuria there is also a direct injurious effect by circulating homocystine, causing endothelial proliferation with or without an admixture of smooth muscle. Furthermore, in pheochromocytoma one must also consider the episodic or sustained hypertension and the direct endothelial effect of the catecholamines in addition to the less familiar but important platelet aggregation. In addition, in thrombotic thrombocytopenic purpura69 and in disseminated intravascular coagulations1 there is widespread platelet aggregation but no notable incidence of focal fibromuscular dysplasia of small coro-

nary arteries. Thus, if platelets play a role in the development, it must be at most a contributory or facilitative one. Abnormal collagen or fibroblast activity: In scleroderma heart diseases2there is not only focal tibromuscular dysplasia of small coronary arteries but also a disproportionately extensive amount of focal fibrosis. In the sinus node that may be particularly severe, occasionally resulting in a totally destructive scirrhous fibrosis, sometimes without significant arterial lesions in the immediate vicinity of the sinus node. If the fibrosing process in scleroderma heart disease is the fault primarily of abnormal behavior by fibroblasts, then one must consider whether the vascular lesions have a similar basis in part or entirely. It was suggested previously that both the esophageal dysfunction in patients with scleroderma and the focal tibromuscular dysplasia of small coronary arteries may be primarily a smooth muscle fault, or the consequence of hyperactivity of the sympathetic nervous system, but both could similarly be due to a fundamental abnormality of collagen or fibroblasts. Additionally, because patients with Marfan’s syndrome have abnormal collagen and also have focal tibromuscular dysplasia of small coronary arteries65 (Fig. 7), there too the vascular abnormality may be caused by the collagen as it is thought to for the aorta. Furthermore, patients with congenital homocystinuria78 characteristically have many features of Marfan’s syndrome and the early differential diagnosis is often difficult, so that in addition to the direct vascular effect of homocystine and its platelet-aggregating action, another possible vascular influence may be abnormal collagen in homocystinuric patients as we11.13s A different significance may be attributed to collagen in the development of focal fibromuscular dysplasia of the sinus node artery or AV node artery, both of which seem somewhat predisposed to it. The sinus node artery is completely encased in the normal fibrous skeleton of the THE AMERICAN

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ies is not rare. Second, there seems to be a predominance of women over men for focal fibromuscular dysplasia of large arteries, especially the renal arteries, whereas I have found no sexual predominance for focal fibromuscular dysplasia of small coronary arteries. Third, suggested hypotheses for the development of focal fibromuscular dysplasia of large arteriesI do not include neural factors, whereas this concept is one of the more appealing theories as to origin of the problem for small coronary arteries. But to suppose that all examples of focal fibromuscular dysplasia, whether found either in large or small arteries and whether involving the heart or other organs, have the same development is probably unreasonable. Nor can we currently say whether focal fibromuscular dysplasia is ever a primary vascular disease, or whether it is always secondary to abnormal nonvascular processes such as neural pathology or collagen disease, or whether these nonvascular factors would not cause focal fibromuscular dysplasia unless a predisposing weakness or fault was present in the artery. As is apparent from the several different plausible mechanisms requiring consideration for the development of focal fibromuscular dysplasia of small coronary arteries in scleroderma, pheochromocytoma and congenital homocystinuria, one should also keep in mind that it is the exceptional heart that exhibits only one type of histologic abnormality in its small coronary arteries. Therefore, in most cases there are probably more than one and sometimes many different causes of focal fibromuscular dysplasia of small coronary arteries, and the principal value of the preceding recitation of possibilities is to call attention to their considerable diversity. FIGURE 7. These photombographs are from adjscent tionrofthednurnodaarteryinaps~dyingwithMarfan’s syndmne. Stfin in B is Vehoeff-van Gibson; the lesion preeomMntlyInthetunicamediabutthefeareirreqguiiZ&bldOf~mCmkaI?S~~.

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sinus node,136 thus limiting its distensibility and possibly influencing any vasa vasorum entering from the adventitia. The normally dense collagen framework of the sinus node may also serve to fix the sinus node artery in place more than is the case for other free-running epicardial atria1 arteries. The AV node artery is similarly fixed in place when it normally penetrates the central fibrous body just after it passes through the AV node.137 Such fmation could place added stress locally,138 and focal fibromuscular dysplasia could represent the histologic response. An analogous consideration has been postulated for mechanical stress from abnormal motion to cause focal fibromuscular dysplasia of renal and carotid arteries.‘3 Multiple

mechanisms

of

development

may

be

the

nrler Despite some histologic similarities, there are several reasons why one should question whether focal fibromuscular dysplasia of large arteries has the same development as that found in small coronary arteries. First, a recent review has suggested that focal fibromuscular dysplasia of large coronary arteries is extremely rare,13 whereas the similar abnormality in small coronary arter206

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Norton WL, Hurd ER, Lewis DC, Ziff M. Evidence of microvascular injury in sclercderma and systemic lupus erythematosus: quantitative study of the microvascular bed. J Lab Clin Med 1968;71:919-933. 39. Opherk D, Mall G, Zebe H, Schwarz F, Weihe E, Manthey J, Kubler W. Reduction of coronary reserve: a mechanism for angina pectoris in patients with arterial hypertension and normal coronary arteries. Circulation J984,69:Jm7. 40. O’Gara PT, Bonow RO, Maron BJ, Damske BA, Van Lingen A, Bacharach SL, Larson SM. Epstein SE. Myocardial perfusion abnormalities in patients with hypertrophic cardiomyopathy: assessment with thallium-201 emission computed tomography. Circulation J987;76:12/4-1223. 41. Nitenberg A, Tavolaro 0, Loisance D, Fault JM, Benhaiem N, Cachera JP. Severe impairment of coronary reserve during rejection in patients with orthotopic heart transplant. Circulation 1989;79:59-65. 42. Schneeweiss A, Sherf L, Lehrer E, Lieberman Y, Neufeld HN. 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Mortibus. XXIII. Rheumatoid arthritis and ankylosing spondylitis. Circulation 1977:55:669-677. 33. James TN. Small arteries of the heart. The 36th George E. Brown Memorial Lecture. Circulation 1977;56:2-14. 83. James TN. De Subitaneis Mortibus. XXV. Sarcoid heart disease. Circulation 1977;56:320-326. 33. James TN. De Subitaneis Mortibus. Diversity of histopathologic correlates of atria1 fibrillation. In: Kulbertus HE, Olsson SB, Schlepper M, eds. Atrial Fibrillation. Sweden: AB Hiissle, M~lttdal 1982:13-32. 31. James TN, Bulkley BH. Abnormalities of the coronary arteries in Whipple’s disease. Am Heart J 1983;105:481-491. 92. James TN, Cobbs BW, Coghlan HC, McCoy WC, Fisch C. Coronary disease, cardioneuropathy, and conduction system abnormalities in the cardiomyopathy of Friedreich’s ataxia. Br Heart J 1987:57:446-457. 33. James TN. De Subitaneis Mortibus: Importance of the interplay between abnormalities found in the conduction system, the small arteries and the neural structures of the heart. In: Rossi L, Matturri L, eds. Conduction System and Nerves of the Heart in Life-and-Death. A Clinicopathological Updating: in press. 34. James TN. The cardiac conduction system in cardiomyopathy and myocarditis. In: Volume 3. Cardiomyopathy Update. Tokyo: Uniuersity of Tokyo Press: in press. 35. James TN. Morphology of the human atrioventricular node, with remarks pertinent to its electrophysiology. Am Heart J 1961,62:756-771. 33. James TN. Anatomy of the human sinus node. Anat Ret 1961;141:109139. 37. James TN. Anatomy of the Coronary Arteries. Harper Brothers, Hagerstown, Maryland, 1961. 38. James TN, Jackson DA. De Subitaneis Mortibus. XXVII. Histological abnormalities in the sinus node, atrioventricular node and His bundle associated with coarctation of the aorta. Circulation 1977;56:1094-1102. 99. Maturi MF, Greene R, Speir E, Burrus C, Dorsey LMA, Markle DR, Maxwell M, Schmidt W, Goldstein SR, Patterson RE. Neuropeptide-Y. A pep tide found in human coronary arteries constricts primarily small coronary arteries to produce myocardial ischemia in dogs. J C/in lnuest 1989;83:1217-1224. 133. MacAlpin RN. Contribution of dynamic vascular wall thickening to luminal narrowing during coronary arterial constriction. Circulation 1980,61:296-301. 101. Araki H, Sakaino N, Furusho N, Nishi K. Longitudinal propagation of contraction in the isolated conduit coronary arteries of humans and pigs. Circ Res 1989.641734-741. 102. Figulla HR. Vetterlein F, Glaubitz M, Kreuzer H. Inhomogenous capillary flow and its prevention by verapamil and hydralazine in the cardiomyopathic Syrian hamster. Circulation 1987:76:208-216, 103. Moncada S, Vane JR. Arachidonic acid metabolites and the interactions between platelets and blood-vessel walls. N Engl J Med 1979:300:1142-l 147. 104. Nitenberg A, Foult JM, Antony I, Blanchet F, Rahali M. Coronary flow and resistance reserve in patients with chronic aortic regurgitation, angina pectoris and normal coronary arteries. JACC 1988:11:478-486. 105. Van Citters RL. Occlusion of lumina in small arterioles during vasoconstriction. Circ Res 1966;18:199-204. 133. Davis RF. Hemodynamics of the coronary circulation. In: Osborne GR, cd. The Incubation Period of Coronary Thrombosis. London Buttenvorths, 1963: 144-154. 107. James TN. Pathogenesis of arrhythmias in acute mywardial infarction. Am J Cardiol 1969;24:791-799, 108. James TN. Mysterious sudden death. Chest 1972,62:454-468. 103. James TN. Chance and sudden death. JACC 1983:1:164-183. 110. James TN. Pulse and impulse in the sinus node. Henry Ford Hasp Med J

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Studies human