Cardiovascular 24 (2015) 335–342

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Cardiovascular Pathology

Perspective : facts and fancy

Michael C. Fishbein ⁎,1, Gregory A. Fishbein

David Geffen School of Medicine at UCLA, Department of Pathology and Laboratory Medicine, Los Angeles, CA 90095 article info abstract

Article history: Arterial vascular diseases comprise the leading cause of in the industrialized world. Every physician learns Received 9 June 2015 about the pathology of these diseases in medical school. All pathologists evaluate arterial disease in surgical Received in revised form 25 July 2015 pathology and/or specimens. All clinicians encounter patients with clinical manifestations of these Accepted 28 July 2015 diseases. With such a common and clinically-important group of entities one would think there would be a general understanding of the “known” information that exists. That is, physicians and scientists should be able Keywords: to separate what is fact and what is fancy. This review article is intended to generate thought in this regard. Arteriosclerosis © 2015 Elsevier Inc. All rights reserved. Arteriolosclerosis Mönckeberg's medial calcificsclerosis Vascular calcification Plaque rupture

1. Introduction hand, both atherosclerosis and Mönckeberg's medial calcific sclerosis are described by Sir Marc Armand Ruffer in his examination of Arterial diseases, namely atherosclerosis and arteriolosclerosis, are Egyptian mummies [6]. So while the terminology is less than 300 arguably the most lethal diseases in industrialized countries leading to years old, the are thousands of years old. Hence the answer to sudden death, myocardial , failure, , , query #1 is: Fancy. and of limbs and major internal organs. In spite of the lesions' Fact or Fancy #2: The current classification of arteriosclerosis is based on importance, there has been little interest in terms, classification, and in a consensus document by a major cardiovascular or pathology organization. our opinion, the true nature of some of the entities under the rubric of Answer #2: Fancy. “arteriosclerosis”. Discussion: The current classification of arteriosclerosis, as defined The purpose of this review is to re-examine the topic of arterioscle- in classic textbooks of pathology (e.g., Robbins [7]), contains three le- rosis in a non-conventional, critical, somewhat tongue-in-cheek, and sions: atherosclerosis, Mönckeberg's medial calcificsclerosis,and perhaps, controversial manner. arteriolosclerosis (Fig. 1). Atherosclerosis is a disease of elastic and Fact or Fancy #1: The lesions of arteriosclerosis are less than 300 years old. large muscular in which the is the characteristic le- Answer #1: Fancy. sion. Mönckeberg's is a calcification process that, according to Discussion: The terms used to describe the lesions of arteriosclerosis Mönckeberg [4] involves only the . Mönckeberg's may be are less than 300 years old. In 1755 Van Haller used the Greek term idiopathic or associated with mellitus and/or renal failure. “atheroma” to describe a space filled with gruel-like material [1].In Arteriolosclerosis is a thickening of the wall of very small arteries, 1833, Frenchman Jean Frederic Martin Lobstein first used the terms those with one or two layers of cells, by intimal “arteriosclerosis” to describe calcified arterial lesions [2]. In 1852, fibromuscular tissue or “hyaline” deposition, typically associated with Johnson described the lesions of “arteriolosclerosis” a thickening of or diabetes. While in recent years efforts have been of the kidney [3]. In 1903, Mönckeberg described “medial cal- made to establish a consensus classification for atherosclerosis [8–11], cific sclerosis” [4]. In 1904 Marchand coined the term atherosclerosis as best we can tell, the current classification of arteriosclerosis comes [5]. Hence, the terms we use today are not very old. On the other from a one page editorial in the American Journal of Clinical Pathology, 24:472–473, 1954, Arteriosclerosis Definitions, by S. M. Rabson, who wrote: Presented at the Society for Cardiovascular Pathology, Annual Companion Meeting, USCAP, March 22, 2015. “May not arteriosclerosis be employed as the generic term covering the ⁎ Corresponding author at: David Geffen School of Medicine at UCLA, Department of condition seen in the and the coronary (atherosclerosis), in Pathology and Laboratory Medicine, 10833 Le Conte Avenue, CHS 13-145, Los Angeles, medial calcification of elastic artery (Mönckeberg's sclerosis), in hyaline CA 90095, USA. 1 Dr. Michael Fishbein is the recipient of the 2015 Distinguished Achievement Award of thickening of the (arteriolosclerosis), to name only the most the Society for Cardiovascular Pathology. prominent disturbances”. As this appears to be the basis of the current http://dx.doi.org/10.1016/j.carpath.2015.07.007 1054-8807/© 2015 Elsevier Inc. All rights reserved. 336 M.C. Fishbein, G.A. Fishbein / Cardiovascular Pathology 24 (2015) 335–342

Fig. 1. Lesions recognized in current classification of arteriosclerosis: (A) atherosclerosis with core (LC) and fibrous cap (FC) (H&E, ×12.5); (B) Mönckeberg's “medial” calcific scle- rosis. Note involvement of internal elastic lamina (arrow) (H&E, ×20); (C) arteriolosclerosis, hyperplastic type, AKA fibromuscular hyperplasia (H&E, ×200); and D) arteriolosclerosis, hyaline type, AKA hyalinosis (H&E, ×100).

classification of arteriosclerosis, the classification is not based on a con- define pathologic patterns, the term arteriolosclerosis does not—aprob- sensus statement by any cardiovascular or pathology organization. lem in the classification. Hence the answer to query #4: Fancy. Hence the answer to query #2: Fancy. Fact or Fancy #5: As was true when Rabson wrote his editorial in 1954 [15], the current classification of arteriosclerosis names the most Fact or Fancy #3: Mönckeberg's medial calcific sclerosis is a disease prominent disturbances. of the media. Answer #5: Fancy. Answer #3: Fancy. Discussion: There are a number of common lesions, both Discussion: This appears to be a silly question, akin to “Who is buried natural and iatrogenic, that cause non-atherosclerotic, primarily in Grant's Tomb?” However, if one examines the literature on this topic, fibromuscular proliferation in the intima of muscular arteries larger one finds that half the references say Mönckeberg's only affects the than arterioles (Fig. 2). The natural lesions include nonspecific media, while the other half of the references state that the intima is intimal thickening, frequently seen in temporal artery biopsies and also involved. Strangely, in the 1961 edition of Anderson's Textbook of other sites. Important iatrogenic lesions include transplant-related Pathology [12], it is stated that in Mönckeberg's, “ is deposited arteriopathy and “ lesions” following balloon and/or in the form of plaques in the mid-portion of the media…” while in . the 1971 edition of the same textbook [13] it states that Mönckeberg's Fact or Fancy #6: While imperfect, the current classification of arte- consists of calcification “involving the media and internal elastic lamina riosclerosis does include all types of arterial calcification. of muscular arteries of the head and neck and extremities”.In Answer #6: Fancy. Mönckeberg's original article there are no photomicrographs or Discussion: While Mönckeberg's sclerosis and atherosclerosis are ar- drawings, but the text states that only the media is involved. In terial lesions with the greatest degree of calcification, another pattern our own study of arteries with lesions diagnosed as Mönckeberg's exists (Fig. 3): calcification limited to the internal elastic lamina is ob- medial sclerosis, 100% of cases had involvement of the internal elas- served and described in temporal arteries, for example. We observed tic lamina [14]. In fact, in less severe cases, it appears that the similar calcification in of HIV positive and control pa- actually begins in the internal elastic lamina and then grows and ex- tients in a study of HIV-related , using specimens tends into the media. Hence, the lesion we call Mönckeberg's medial from our AIDS tissue bank [16]. To our surprise, we could find no prior sclerosis is not purely a medial lesion, and apparently is not the le- reference to this pattern in coronary arteries. sion described by Mönckeberg. Therefore the answer to query #3 Also surprising was the fact that this calcification was not associated is: Fancy. with renal failure, diabetes mellitus, or disorders associated with Fact or Fancy #4: The third category, arteriolosclerosis, defines a abnormal calcium levels. What about calciphylaxis? Calciphylaxis is un- specific pathogenic entity affecting small arteries. doubtedly a process that causes hardening of the arteries. Nevertheless, Answer #4: Fancy. classic textbooks of pathology do not include calciphylaxis in the classi- Discussion: The term arteriolosclerosis actually does not define a fication of arteriosclerosis. Based on the fact that calciphylaxis is a form lesion at all. It is a generic term meaning “hardening of small arteries”. of vascular calcification, and calciphylaxis is not covered in the current In fact, the term encompasses two distinct lesions: 1) a fibromuscular classification, the answer to query #6: Fancy. proliferation of the intima, the “hyperplastic type”, and 2) a deposition Since there are entities, such as those heretofore described, that of amorphous material in the arteriolar wall, the “hyaline type”.Unlike cause hardening of the arteries but are not considered arteriosclerosis, the two terms atherosclerosis and Mönckeberg's medial sclerosis that we urge consideration of a new, more comprehensive, accurate M.C. Fishbein, G.A. Fishbein / Cardiovascular Pathology 24 (2015) 335–342 337

These are regions with intimal smooth muscle and that demonstrate increased turnover of smooth muscle cells and endo- thelial cells, increased permeability, increased concentration of low density , and low shear stress and/or high wall tensile stress. So the progression and evaluation of clinically-significant athero- sclerotic plaques may not involve the . Hence the answer to query #7: Fancy. Fact or Fancy #8: Atherosclerosis is a primary inflammatory disease. Answer #8: Fancy. Discussion: It is difficult to pick up a contemporary article on athero- sclerosis that does not begin with the statement that “atherosclerosis is an inflammatory disease”. There is no question that inflammation plays a role in the progression and complications of atherosclerosis [18]. Ath- erosclerosis has also been thought to be an infectious disease [19],ade- generative disease [20], a thrombogenic disease [20], and even a primary proliferative disease [21]. However, it is also quite clear and has been understood for over 100 years that the first event in athero- genesis is low density lipoproteins entering the arterial wall [22].Itis the presence of these lipoproteins that become oxidized that initiates the inflammation seen in atherosclerotic plaques [23]. Furthermore, major studies of atherosclerosis, such as the MRFIT study, always show a relationship between the frequency of coronary events and cho- lesterol levels. Populations that have low levels have fewer coronary events [24–27]. Hence atherosclerosis is a primary disease of , not inflamma- tion, so the answer to query #8: Fancy. Fact of Fancy #9: The concept that inflammation plays a role in the progression of atherosclerosis is a new idea. Answer #9: Fancy. Discussion: Recent research work has identified molecular and cel- lular pathways of inflammation that participate in the process of athero- sclerosis [28]. While contemporary investigators continue to elucidate the details of the inflammatory response in atherosclerotic disease, past investigators have noted the inflammation and its importance in the progression and complications of atherosclerosis. In 1856 Rudolf Virchow introduced the term “endarteritis chronica” to describe athero- sclerosis, ascribing atheroma formation to chronic irritation—an inflam- matory process [29]. In 1928, in a paper entitled “An inflammatory basis for coronary ” [30], A.N. Boyd stated that “…an atheroscle- rotic plaque may suddenly undergo an acute degeneration associated with inflammation and that thrombosis may be the result.” Hence the answer to query #9: Fancy. Fact or Fancy #10: Current known risk factors can reliably identify Fig. 2. Other lesions not in the current classification of arteriosclerosis: (A) temporal artery of elderly male with nonspecific intimal hyperplasia (I) (H&E, ×100); (B) intramyocardial individuals at increased risk of a coronary event. artery with allograft vasculopathy manifest as marked fibromuscular intimal hyperplasia Answer #10: Fancy. (H&E, ×100); and (C) coronary artery stent with “neointima” (arrow) covering stent Discussion: Table 1 lists generally accepted risk factors for coronary (toluidine blue, ×12.5). events, but we all have seen cases where patients have no risk factors, yet have severe atherosclerosis, while other patients have multiple classification. We previously published a suggested start for efforts in risk factors, yet have no clinically significant disease. Epidemiologists that direction [17] (Fig. 4). tell us that risk factors account for about 50% of the risk of an event Fact or Fancy #7: Clinically-significant atherosclerotic plaques [31]. Furthermore, new risk factors are being identified all the time originate as fatty streaks, then progress to fibrous plaques, and finally (Table 2). Exposure to particulate matter in the atmosphere (i.e. air pol- progress to the only clinically-significant plaques, the complicated plaque. lution) has been associated with an increased risk of a coronary event Answer #7: Fancy. [35]. This observation adds new meaning to the phrase “living in a Discussion: While the standard teaching is that clinically-significant safe neighborhood.” More recently and more irritating is the finding atherosclerotic plaques begin in fatty streaks, investigators have that it is not only our , but also the way our intestinal questioned this evolution [1]. Basically, all that fatty streaks and compli- microbiota metabolize our food that promotes atherosclerosis [36]. cated plaques have in common is lipid. Racial groups that are born with Apparently our intestinal bacteria metabolize certain foods we eat, more fatty streaks in the aorta have fewer complicated plaques. Fatty releasing pro-atherogenic compounds in our vascular system. So it is streaks in the aorta are most often posterior midline, while raised not our metabolism, but that of our intestinal bacteria that may plaques are more often anterior and lateral. Fatty streaks are more com- determine whether or not atherosclerosis develops. To add injury to in- mon in the proximal aorta, while raised plaques are more common in sult, now, genetically-determined short stature has been shown to be a the distal aorta. Mouths of intercostal arteries are usually free of fatty for [34]. Sometimes our genes just streaks, but raised plaques often develop at that site. Furthermore, conspire against us. the most important raised plaques, those that develop in coronary arter- The above are examples of novel discoveries that are identifying new ies, develop in regions of adaptive intimal thickening (AIT) (Fig. 5). risk factors. Hence, the answer to query #10: Fancy. 338 M.C. Fishbein, G.A. Fishbein / Cardiovascular Pathology 24 (2015) 335–342

Fig. 3. Patterns of arterial calcification: (A) intimal calcification (Ca) within an atherosclerotic plaque (H&E, ×20); (B) so-called Mönckeberg's medial sclerosis with calcification of the media and internal elastic lamina (arrow) (H&E, ×100); (C) temporal artery from elderly male (H&E, ×100); (D) artery from lower extremity in a patient with calciphylaxis (H&E, ×40); (E) coronary artery with calcification of the internal elastic lamina (arrows) from HIV positive patient (H&E, ×100); and (F) Alizarin red S stain of artery shown in (E) (×100).

Fact or Fancy #11: Currently, there is a comprehensive understand- sudden cardiac death or due to atherosclerotic ing about the “vulnerable” atherosclerotic plaque and why it ruptures. coronary artery disease [37]. Indeed, he reported acute changes in the Answer #11: Fancy. “culprit” lesion in over 75% of such cases. To give credit where credit is Discussion: There is a consensus regarding the definition of a vulner- due, we should acknowledge that a number of investigators before able atherosclerotic plaque; however, there are major gaps in our Davies tried to promote the same concept [30,38–49] (Table 3), but knowledge about such plaques. Generally speaking, a vulnerable ath- the concept never really caught on until Davies' publication. Hence the erosclerotic plaque is one that is at high risk of rupture and/or one answer to query #12 is: Fancy. that is thrombosis prone. Once the plaque ruptures, the antithrombotic Fact or Fancy #13: A disproportionate number of plaque ruptures is injured and the pro-thrombotic contents of the plaque occur in the shoulder region of the plaque. are exposed to the circulating blood promoting thrombosis at the site Answer #13: Fancy. of intimal disruption. Histologically, the is an in- Discussion: Much of the current investigation of vulnerable plaques flamed, thin-cap fibroatheroma with a large lipid core. It should be involves study of the shoulder region of the plaque, the site believed to kept in mind that the association of this histologic pattern to plaque be most susceptible to rupture. What is the basis for this perception? rupture is just that—an association. There is no established cause/effect Perhaps the most often cited work promoting this concept comes relationship, in great part due to the lack of a reliable experimental from a paper by Richardson, Davies, and Born in Lancet in 1989 [50]. model that mimics the human situation. Hence the answer to query The authors reported that of 67 plaques with an eccentric lipid pool, #11: Fancy. 42 (63%) had torn at the junction of the plaque cap with the adjacent Fact or Fancy #12: The relationship between coronary artery plaque normal intima, and 25 (37%) through the center of the cap. Thus it rupture and thrombosis is a relatively new discovery. appears that 2/3 of plaque ruptures involve the shoulder. While that Answer #12: Fancy. may be true, in cross-section, the plaques described would have one Discussion: In a number of related papers in the 1980s and 1990s, central region and two shoulders (Fig. 6). Therefore if plaque rupture Dr. Michael Davies “revived” the notion that plaque rupture leading to were a random event in such plaques, 2/3 would involve the shoulder thrombosis was the predominant finding in patients who suffered region and 1/3 the central region. Accordingly, if indeed there is M.C. Fishbein, G.A. Fishbein / Cardiovascular Pathology 24 (2015) 335–342 339

Table 1 Generally-recognized risk factors for atherosclerosis

Age Fibrinogen level Gender Lipid level/diet Family history Hypertension Type A personality Emotional stress Diabetes mellitus Gout

Table 2 Novel risk factors for atherosclerosis

Air pollution [32] Metabolism of intestinal microbiota [33] Short stature [34]

Fact or Fancy #14: “Non-stenotic lesions account for the majority of culprit ruptured plaques [51]”. Answer #14: Fancy. Discussion: There has been the general notion that the smaller, non- occlusive plaque ruptures more frequently than large occlusive plaques, and that most coronary events are related to such smaller plaques. What is the basis for this concept? There have been a number of angiographic studies in patients who had coronary months before, and immediately after, a coronary event [52–57]. According to the authors, before the coronary event, the culprit lesions were actually small non- occlusive plaques. If one actually looks at the data from these studies (Table 4), about 50% of the culprit lesions showed less than 50% diame- ter (equal to 75% cross-sectional area stenosis). These findings are different from pathologic studies of fatal myocardial coronary events [49,58–60] (Fig. 7). In these pathologic studies (Table 5), only 14% of plaque rupture with thrombosis occurred in arteries with less than 75% cross-sectional narrowing. The angiographic studies were

Fig. 4. Current and proposed classifications of arteriosclerosis. Mönckeberg’s sclerosis questioned years ago (see Fishbein MC, Siegel RJ. How big are coronary should be included in a broader category that encompass the different patterns of arterial atherosclerotic plaques that rupture? [61]). However, only recently, calcification. with the advent of novel, better imaging modalities, has the paradigm shifted. In the COURAGE trial [62], 2287 patients with stable coronary something special about the shoulder region, the data from this study artery were randomized to either optimal medical therapy or percuta- do not really establish that the number of ruptures in the shoulder neous intervention and medical therapy. In patients randomized to region is greater than were it a completely random process. Hence the medical therapy who had a coronary event, the majority of responsible answer to query #13: Fancy. lesions had greater than 50% diameter narrowing at the time of

Fig. 5. Atheroma precursor lesions: A) fatty streak consisting primarily of lipid-laden (arrows) (H&E, ×200); and B) proximal coronary artery with adaptive intimal thick- ening showing fracture in internal elastic lamina (arrow), as well as intimal hyperplasia (I) (Movat pentachrome, ×100). 340 M.C. Fishbein, G.A. Fishbein / Cardiovascular Pathology 24 (2015) 335–342

Table 3 Table 4 Articles with reference to plaque rupture and thrombosis Severity of stenosis in atherosclerotic plaques that rupture: angiographic studies

1926 – Benson [38] 1940 – Horn [43] Author #pts Interval from first to % diameter stenosis 1928 – Boyd [30] 1965 – Fulton [42] second angiogram (months) before MI (#pts) 1932 – Koch [44] 1965 – Chapman [39] b50% 51–75% N75% 1934 – Leary [45] 1966 – Friedman [41] 1935 – Saphir [48] 1977 – Ridolfi [47] Ambrose [52] 23 18 12 6 5 1938 – Paterson [46] 1984 – Davies [49] Giroud [53] 92 24 72 8 12 1936 – Clark [40] Hackett [54] 10 21 9 1 0 Little [55] 58 24 36 15 7 Moise [56] 116 39 17 66 33 Webster [57] 30 55 16 10 4 randomization. Very few events were due to progression of lesions that Totals 329 30 162 106 61 had less than 50% diameter narrowing [63]. (49%) (32%) (19%) A more recent study by Tuan et al. using OCT, IVUS, and angiography also found that most “vulnerable” thin-cap fibroatheromas were pre- sent in more, rather than less, stenotic regions. Fig. 6b demonstrates how a plaque rupture might appear to be occurring in a small plaque. the Brazilian team's matches during World Cup soccer in 1998, 2002, If the rupture occurs at the shoulder of the plaque, that is likely not 2006, and 2010 [66]. Similarly, in England, admissions for acute myocar- the region of maximum narrowing of the plaque, which, in the diagram, dial infarction increased by 25% on June 30, 1998—the day England lost a is more downstream. This phenomenon has been documented in angio- World Cup soccer match to Argentina in a penalty shoot-out [67]. While graphic studies [64]. there are undoubtedly cardiovascular benefits to playing competitive Hence, the answer to query #14: Fancy. soccer, the data are clear—spectators are at increased risk. So indeed, A major, perhaps the major question concerning plaque rupture is, the answer to query #15: Fact. Watching soccer causes plaque rupture. “why does rupture occur when it does?” Unfortunately, we don't have a good experimental model, and it is probably impossible to study this experimentally in man, so we have to rely on epidemiologic data. Acknowledgments So far the answer to all 14 questions so far, in our opinion, is Fancy. Fact or Fancy #15: Watching soccer causes plaque rupture. The authors wish to acknowledge the expert editorial assistance of Answer #15: (Believe it or not!) Fact. Ms. Leslie Chew and the expert technical skills of Ms. Longsheng Hong. Discussion: Wilbert-Lampen et al. reviewed the number of coronary events in Germany during the World Cup Soccer Tournament in 2003, References 2005, and 2006 [65]. The authors observed spikes in the number of events that all occurred on days the German soccer team played a [1] Schwartz CJ, Mitchell JRA. The Morphology, Terminology and Pathogenesis of Arterial Plaques. 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Fig. 7. (A–F) Examples of culprit coronary arteries from patients with sudden cardiac death. Note arteries narrowed by large atherosclerotic plaques with occlusive luminal thrombus (T) (all H&E, ×12.5).

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