Translational Sciences Prevalence of Nonatheromatous Lesions in Peripheral Arterial Disease W. Charles O’Neill, Kum Hyun Han, Thomas M. Schneider, Randolph A. Hennigar Objective—The histopathology of peripheral arterial disease and the accompanying calcification are poorly defined, and it is not known whether this varies according to different risk factors. Approach and Results—Sections from 176 upper and lower leg arteries were examined histologically in specimens from amputations of 60 patients with peripheral arterial disease, of whom 58% had diabetes mellitus, 35% had end-stage renal disease, and 48% had a history of smoking. The most common findings were calcification of the media (72% of arteries) and intimal thickening without lipid (68% of arteries), with the presence of atheromas in only 23% of arteries. Intimal calcification occurred in 43% and was generally much less extensive than medial calcification. Nonatheromatous intimal thickening was frequently severe, resulting in complete occlusion in some vessels. The absence of lipid and macrophages was confirmed by staining with oil red O and staining for CD68. Other than a greater prevalence and severity of medial calcification in end-stage renal disease, the findings did not differ between diabetics, patients with end-stage renal disease, or smokers. Conclusions—The results indicate that the majority of arteries in patients with peripheral arterial disease have a vascular lesion that is distinct from atherosclerosis, suggesting a different pathogenesis. This pattern does not differ substantially between patients with different risk factors for peripheral arterial disease. The bulk of vascular calcification in the lower extremities is medial rather than intimal. (Arterioscler Thromb Vasc Biol. 2015;35:439-447. DOI: 10.1161/ATVBAHA.114.304764.) Key Words: arteriosclerosis ◼ atherosclerosis ◼ pathology ◼ peripheral vascular diseases ◼ vascular calcification
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eripheral arterial disease (PAD) is a serious condition that is responsible for substantial morbidity, disability, and costs.1 Because it is not a direct cause of death, it is not included in the end-point of cardiovascular death used in many clinical studies, and therefore, it remains understudied. Diabetes mellitus, smoking, and end-stage renal disease (ESRD) are all independent risk factors,2,3 and the frequent coexistence of diabetes mellitus and ESRD leads to high rates of PAD. Because PAD shares many risk factors with coronary artery disease, it is widely assumed to be atherosclerotic in nature and is treated as a similar event in most studies. The pathophysiological and therapeutic approach to PAD is also based on this assumption. However, although there is an abundance of histological studies documenting the atherosclerotic process in coronary arteries, such data are lacking in peripheral arteries. Furthermore, it is not known whether the histology differs between risk factors. Such data would be important in defining the pathophysiology and natural history of PAD, perhaps leading to more specific therapies. Arterial calcification is increasingly recognized as a clinically important disorder, but understanding its causes and clinical significance is hampered by the fact that it represents 2 distinct disorders, medial calcification (also known as
Monckeberg’s arteriosclerosis) and intimal (atherosclerotic) calcification, that frequently coexist. The fact that the relative frequencies probably vary between vascular beds and different conditions, such as diabetes mellitus and ESRD,4–6 leads to further difficulty in interpreting clinical data. Calcification of lower extremity arteries is common in PAD and predicts a worse prognosis,7 but it is not known whether this calcification is medial or intimal. Whether the increased risk of PAD in ESRD is because of altered mineral metabolism and resulting vascular calcification is also unknown. In the course of studying vascular calcification in arteries from patients with ESRD undergoing lower-extremity amputation, we found a high prevalence of medial arterial calcification and a surprisingly low frequency of advanced atherosclerosis. This led us to investigate other patients with PAD and to investigate in more detail the nonatheromatous lesions in these arteries. The results suggest that the pathology of PAD differs from the atherosclerosis classically described in coronary arteries.
Materials and Methods Materials and Methods are available in the online-only Data Supplement.
Received on: March 26, 2014; final version accepted on: November 7, 2014. From the Renal Division, Department of Medicine (W.C.O., K.H.H.), and Department of Pathology (T.M.S., R.A.H.), Emory University School of Medicine, Atlanta, GA; and Department of Internal Medicine, Inje University College of Medicine, Ilsan Paik Hospital, Goyang, Korea (K.H.H.). The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/doi:10.1161/ATVBAHA.114.304764/-/DC1. Correspondence to W. Charles O’Neill, MD, Renal Division, Emory University, WMB 338, 1639 Pierce Dr, Atlanta, GA 30322. E-mail [email protected] © 2014 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org
439
DOI: 10.1161/ATVBAHA.114.304764
440 Arterioscler Thromb Vasc Biol February 2015 lipoprotein cholesterol in patients with intimal inflammation, there was no association with serum lipoproteins and intimal lipid or inflammation (Table II in the online-only Data Supplement). Evidence of lipid (usually in the form of intimal foam cells) was found in only a quarter of the sections with thickened intimas. Of these 41, 19 had type I or II lesions (Figure 2A), 20 had type V lesions (Figure 2B) and 1 had an intermediate lesion according to the standard classification.8 Intimal lipid was found in arteries from 28 patients, but it was absent in all arteries from 32 patients. Of the 52 patients with >1 artery examined, intimal lipid was absent in all arteries from 26 patients, whereas only 2 patients had lipid in all arteries. The absence of lipid was more frequent in arteries below the knees and was associated with a younger patient age (63.9±1.3 versus 69.1±2.1, P1 risk factor. Detailed characteristics of the patients are shown in Table I in the online-only Data Supplement. Other than the reduced prevalence of smoking in the ESRD patients, there were no significant differences between the groups. Only 4 patients did not have diabetes mellitus, ESRD, or a smoking history. Of the 15 patients receiving warfarin at the time of the amputation, 7 had atrial fibrillation, 4 had thrombotic disease, and 2 had mechanical heart valves. In the remaining 2, the indication was critical limb ischemia.
Histopathology of the Intima The distribution of arteries examined and the histological findings in the intima are shown in Table 1. Many sections were labeled as margins, or proximal or distal, precluding the identification of specific arteries. Specimens frequently contained both tibial arteries, which could not be distinguished, and the peroneal artery was identified in only 4 specimens and was not analyzed separately. Because of the limited numbers of specific arteries, reliable comparisons could be made only between arteries above and below the knee. Intimal thickening was present in >90% of vessels (concentric in most cases) and did not differ between arteries above and below the knee. Thickening was associated with a greater patient age (66.0±1.2 versus 56.8±2.8 years; P
P
eripheral arterial disease (PAD) is a serious condition that is responsible for substantial morbidity, disability, and costs.1 Because it is not a direct cause of death, it is not included in the end-point of cardiovascular death used in many clinical studies, and therefore, it remains understudied. Diabetes mellitus, smoking, and end-stage renal disease (ESRD) are all independent risk factors,2,3 and the frequent coexistence of diabetes mellitus and ESRD leads to high rates of PAD. Because PAD shares many risk factors with coronary artery disease, it is widely assumed to be atherosclerotic in nature and is treated as a similar event in most studies. The pathophysiological and therapeutic approach to PAD is also based on this assumption. However, although there is an abundance of histological studies documenting the atherosclerotic process in coronary arteries, such data are lacking in peripheral arteries. Furthermore, it is not known whether the histology differs between risk factors. Such data would be important in defining the pathophysiology and natural history of PAD, perhaps leading to more specific therapies. Arterial calcification is increasingly recognized as a clinically important disorder, but understanding its causes and clinical significance is hampered by the fact that it represents 2 distinct disorders, medial calcification (also known as
Monckeberg’s arteriosclerosis) and intimal (atherosclerotic) calcification, that frequently coexist. The fact that the relative frequencies probably vary between vascular beds and different conditions, such as diabetes mellitus and ESRD,4–6 leads to further difficulty in interpreting clinical data. Calcification of lower extremity arteries is common in PAD and predicts a worse prognosis,7 but it is not known whether this calcification is medial or intimal. Whether the increased risk of PAD in ESRD is because of altered mineral metabolism and resulting vascular calcification is also unknown. In the course of studying vascular calcification in arteries from patients with ESRD undergoing lower-extremity amputation, we found a high prevalence of medial arterial calcification and a surprisingly low frequency of advanced atherosclerosis. This led us to investigate other patients with PAD and to investigate in more detail the nonatheromatous lesions in these arteries. The results suggest that the pathology of PAD differs from the atherosclerosis classically described in coronary arteries.
Materials and Methods Materials and Methods are available in the online-only Data Supplement.
Received on: March 26, 2014; final version accepted on: November 7, 2014. From the Renal Division, Department of Medicine (W.C.O., K.H.H.), and Department of Pathology (T.M.S., R.A.H.), Emory University School of Medicine, Atlanta, GA; and Department of Internal Medicine, Inje University College of Medicine, Ilsan Paik Hospital, Goyang, Korea (K.H.H.). The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/doi:10.1161/ATVBAHA.114.304764/-/DC1. Correspondence to W. Charles O’Neill, MD, Renal Division, Emory University, WMB 338, 1639 Pierce Dr, Atlanta, GA 30322. E-mail [email protected] © 2014 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org
439
DOI: 10.1161/ATVBAHA.114.304764
440 Arterioscler Thromb Vasc Biol February 2015 lipoprotein cholesterol in patients with intimal inflammation, there was no association with serum lipoproteins and intimal lipid or inflammation (Table II in the online-only Data Supplement). Evidence of lipid (usually in the form of intimal foam cells) was found in only a quarter of the sections with thickened intimas. Of these 41, 19 had type I or II lesions (Figure 2A), 20 had type V lesions (Figure 2B) and 1 had an intermediate lesion according to the standard classification.8 Intimal lipid was found in arteries from 28 patients, but it was absent in all arteries from 32 patients. Of the 52 patients with >1 artery examined, intimal lipid was absent in all arteries from 26 patients, whereas only 2 patients had lipid in all arteries. The absence of lipid was more frequent in arteries below the knees and was associated with a younger patient age (63.9±1.3 versus 69.1±2.1, P1 risk factor. Detailed characteristics of the patients are shown in Table I in the online-only Data Supplement. Other than the reduced prevalence of smoking in the ESRD patients, there were no significant differences between the groups. Only 4 patients did not have diabetes mellitus, ESRD, or a smoking history. Of the 15 patients receiving warfarin at the time of the amputation, 7 had atrial fibrillation, 4 had thrombotic disease, and 2 had mechanical heart valves. In the remaining 2, the indication was critical limb ischemia.
Histopathology of the Intima The distribution of arteries examined and the histological findings in the intima are shown in Table 1. Many sections were labeled as margins, or proximal or distal, precluding the identification of specific arteries. Specimens frequently contained both tibial arteries, which could not be distinguished, and the peroneal artery was identified in only 4 specimens and was not analyzed separately. Because of the limited numbers of specific arteries, reliable comparisons could be made only between arteries above and below the knee. Intimal thickening was present in >90% of vessels (concentric in most cases) and did not differ between arteries above and below the knee. Thickening was associated with a greater patient age (66.0±1.2 versus 56.8±2.8 years; P
