Arteriosclerosis and atherosclerosis of the lower limbs and cardiovascular risk

In this issue of Atherosclerosis, Stone et al. describe the associations of lower limb atherosclerosis, measured as ankle brachial index (ABI) and of arteriosclerosis, measured as femoral-ankle pulse wave velocity (faPWV), with cardiovascular (CV) risk [[1]Stone K. Fryer S. Faulkner J. Hughes T.M. Tanaka H. Stoner L. et al.Associations of lower-limb atherosclerosis and arteriosclerosis with cardiovascular risk factors and disease in older adults: the atherosclerosis risk in communities (ARIC) study.Atherosclerosis. 2021; https://doi.org/10.1016/j.atherosclerosis.2021.10.014Abstract Full Text Full Text PDF Scopus (1) Google Scholar]. In our commentary, we briefly discuss the slightly confusing use of the terms arteriosclerosis and atherosclerosis, and offer a perspective on the prognostic meaning of faPWV and ABI. Not long ago, atherosclerosis and arteriosclerosis were used interchangeably, although they nowadays denote different vascular pathologies [[2]Santos V.P. Pozzan G. Castelli Junior V. Caffaro R.A. Arteriosclerosis, atherosclerosis, arteriolosclerosis, and Monckeberg medial calcific sclerosis: what is the difference?.J. Vasc. Bras. 2021; 20e20200211https://doi.org/10.1590/1677-5449.200211Crossref PubMed Scopus (2) Google Scholar]. In atherosclerosis, the leading process is low-grade inflammation, leading to focal narrowing of the arterial lumen by deposition of inflammatory cells and cholesterol, and by proliferation of smooth muscle cells in the intima layer [[3]Ross R. Atherosclerosis – an inflammatory disease.N. Engl. J. Med. 1999; 340: 115-126https://doi.org/10.1056/NEJM199901143400207Crossref PubMed Scopus (18680) Google Scholar,[4]Libby P. Ridker P.M. Hansson G.K. Leducq Transatlantic Network on AtherothrombosisInflammation in atherosclerosis: from pathophysiology to practice.J. Am. Coll. Cardiol. 2009; 54: 2129-2138https://doi.org/10.1016/j.jacc.2009.09.009Crossref PubMed Scopus (1435) Google Scholar]. Arteriosclerosis denotes thickening and hardening (stiffening) of the arterial wall due to elastin degradation and collagen deposition in the media layer [[2]Santos V.P. Pozzan G. Castelli Junior V. Caffaro R.A. Arteriosclerosis, atherosclerosis, arteriolosclerosis, and Monckeberg medial calcific sclerosis: what is the difference?.J. Vasc. Bras. 2021; 20e20200211https://doi.org/10.1590/1677-5449.200211Crossref PubMed Scopus (2) Google Scholar,[5]Fishbein G.A. Fishbein M.C. Arteriosclerosis: rethinking the current classification.Arch. Pathol. Lab Med. 2009; 133: 1309-1316https://doi.org/10.5858/133.8.1309Crossref PubMed Google Scholar]. The term arteriosclerosis may be used broadly to describe any kind of increased arterial stiffness – as in the paper of Stone et al. [[1]Stone K. Fryer S. Faulkner J. Hughes T.M. Tanaka H. Stoner L. et al.Associations of lower-limb atherosclerosis and arteriosclerosis with cardiovascular risk factors and disease in older adults: the atherosclerosis risk in communities (ARIC) study.Atherosclerosis. 2021; https://doi.org/10.1016/j.atherosclerosis.2021.10.014Abstract Full Text Full Text PDF Scopus (1) Google Scholar], or it may be used as a collective term for two specific disorders: Mönckeberg medial calcific sclerosis (MCC) and arteriolosclerosis [[2]Santos V.P. Pozzan G. Castelli Junior V. Caffaro R.A. Arteriosclerosis, atherosclerosis, arteriolosclerosis, and Monckeberg medial calcific sclerosis: what is the difference?.J. Vasc. Bras. 2021; 20e20200211https://doi.org/10.1590/1677-5449.200211Crossref PubMed Scopus (2) Google Scholar,[5]Fishbein G.A. Fishbein M.C. Arteriosclerosis: rethinking the current classification.Arch. Pathol. Lab Med. 2009; 133: 1309-1316https://doi.org/10.5858/133.8.1309Crossref PubMed Google Scholar]. MCC denotes the calcification of the media and internal elastic lamina, which is often associated with diabetes mellitus, kidney disease and advanced age [[2]Santos V.P. Pozzan G. Castelli Junior V. Caffaro R.A. Arteriosclerosis, atherosclerosis, arteriolosclerosis, and Monckeberg medial calcific sclerosis: what is the difference?.J. Vasc. Bras. 2021; 20e20200211https://doi.org/10.1590/1677-5449.200211Crossref PubMed Scopus (2) Google Scholar,[5]Fishbein G.A. Fishbein M.C. Arteriosclerosis: rethinking the current classification.Arch. Pathol. Lab Med. 2009; 133: 1309-1316https://doi.org/10.5858/133.8.1309Crossref PubMed Google Scholar,[6]Gherman D. Dumitrescu C.I. Ciocan A. Melincovici C.S. Histopathological changes in major amputations due to diabetic foot – a review.Rom. J. Morphol. Embryol. 2018; 59 (PMID:30534807): 699-702PubMed Google Scholar]. MCC alone does not manifest as an obstructive lesion, but it may coexist with obstructive atherosclerosis [[7]Ho C.Y. Shanahan C.M. Medial arterial calcification: an overlooked player in peripheral arterial disease.Arterioscler. Thromb. Vasc. Biol. 2016; 36: 1475-1482https://doi.org/10.1161/ATVBAHA.116.306717Crossref PubMed Scopus (90) Google Scholar]. Arteriolosclerosis denotes thickening of the microcirculatory arterioles. There are two types of arteriolar thickening: hyaline arteriolosclerosis and hyperplastic arteriolosclerosis [[2]Santos V.P. Pozzan G. Castelli Junior V. Caffaro R.A. Arteriosclerosis, atherosclerosis, arteriolosclerosis, and Monckeberg medial calcific sclerosis: what is the difference?.J. Vasc. Bras. 2021; 20e20200211https://doi.org/10.1590/1677-5449.200211Crossref PubMed Scopus (2) Google Scholar,8Kono K. Fujii H. Nakai K. Goto S. Watanabe S. Watanabe K. et al.Relationship between type of Hypertension and Renal Arteriolosclerosis in chronic glomerular disease.Kidney Blood Press. Res. 2016; 41: 374-383https://doi.org/10.1159/000443440Crossref PubMed Scopus (9) Google Scholar, 9Ighodaro E.T. Abner E.L. Fardo D.W. Lin A.-L. Katsumata Y. Schmitt F.A. et al.Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals.J. Cerebr. Blood Flow Metabol. 2017; 37: 201-216https://doi.org/10.1177/0271678X15621574Crossref PubMed Scopus (40) Google Scholar, 10Hill G.S. Hypertensive nephrosclerosis.Curr. Opin. Nephrol. Hypertens. 2008; 17: 266-270https://doi.org/10.1097/MNH.0b013e3282f88a1fCrossref PubMed Scopus (123) Google Scholar]. Hyaline arteriolosclerosis is predominantly associated with arterial hypertension and affects the kidney, leading to glomerulosclerosis [[8]Kono K. Fujii H. Nakai K. Goto S. Watanabe S. Watanabe K. et al.Relationship between type of Hypertension and Renal Arteriolosclerosis in chronic glomerular disease.Kidney Blood Press. Res. 2016; 41: 374-383https://doi.org/10.1159/000443440Crossref PubMed Scopus (9) Google Scholar], and the brain, leading to intraparenchymal hemorrhages and cognitive impairment [[9]Ighodaro E.T. Abner E.L. Fardo D.W. Lin A.-L. Katsumata Y. Schmitt F.A. et al.Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals.J. Cerebr. Blood Flow Metabol. 2017; 37: 201-216https://doi.org/10.1177/0271678X15621574Crossref PubMed Scopus (40) Google Scholar]. Hyperplastic arteriolosclerosis, associated with severe arterial hypertension, causes significant reduction of arteriolar lumen due to thickening of smooth muscles and basement membranes [[10]Hill G.S. Hypertensive nephrosclerosis.Curr. Opin. Nephrol. Hypertens. 2008; 17: 266-270https://doi.org/10.1097/MNH.0b013e3282f88a1fCrossref PubMed Scopus (123) Google Scholar]. To some extent, all of the pathologies mentioned above are interrelated by sharing similar risk factors. However, in addition to differences in pathomorphology, atherosclerosis and arteriosclerosis differ somewhat in the prognostic meaning for CV events. While the association of low ABI and CV risk is well known and therefore not at all surprising, the inverse association between femoral-ankle pulse wave velocity (faPWV) and CVD risk in the ARIC Study population [[1]Stone K. Fryer S. Faulkner J. Hughes T.M. Tanaka H. Stoner L. et al.Associations of lower-limb atherosclerosis and arteriosclerosis with cardiovascular risk factors and disease in older adults: the atherosclerosis risk in communities (ARIC) study.Atherosclerosis. 2021; https://doi.org/10.1016/j.atherosclerosis.2021.10.014Abstract Full Text Full Text PDF Scopus (1) Google Scholar] might seem counterintuitive to many clinicians. Most of the published data on prognostic significance of arterial stiffness is based on carotid-femoral pulse wave velocity, which is a measure of aortic stiffness. Uniformly, a positive association between aortic stiffness and CVD risk has been described [11Blacher J. Guerin A.P. Pannier B. Marchais S.J. Safar M.E. London G.M. Impact of aortic stiffness on survival in end-stage renal disease.Circulation. 1999; 99: 2434-2439https://doi.org/10.1161/01.CIR.99.18.2434Crossref PubMed Scopus (1811) Google Scholar, 12Laurent S. Boutouyrie P. Asmar R. Gautier I. Laloux B. Guize L. Ducimetiere P. Benetos A. Aortic stiffness is an independent predictor of all cause and cardiovascular mortality in hypertensive patients.Hypertension. 2001; 37: 1236-1241https://doi.org/10.1161/01.HYP.37.5.1236Crossref PubMed Scopus (2979) Google Scholar, 13Boutouyrie P. Tropeano A.I. Asmar R. Gautier I. Benetos A. Lacolley P. Laurent S. Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study.Hypertension. 2002; 39: 10-15https://doi.org/10.1161/hy0102.099031Crossref PubMed Scopus (1433) Google Scholar, 14Willum-Hansen T. Staessen J.A. Torp-Pedersen C. Rasmussen S. Thijs L. Ibsen H. Jeppesen J. Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population.Circulation. 2006; 113: 664-670http://circ.ahajournals.org/content/113/5/664Crossref PubMed Scopus (1140) Google Scholar]. While the aorta is an elastic artery, the femoral, popliteal and calf arteries are muscular arteries and their stiffness, i.e., faPWV has been less well studied [[15]Schillaci G. Pucci G. Lower-limb pulse wave velocity: correlations and clinical value.Hypertens. Res. 2013; 36: 679-681https://doi.org/10.1038/hr.2013.47Crossref PubMed Scopus (3) Google Scholar]. In the post-MONICA study of the general population, faPWV was higher than carotid-femoral PWV especially in younger individuals, and the PWV gradient between the aorta and the lower-limb arteries decreased with age [[16]Wohlfahrt P. Krajčoviechova A. Seidlerova J. Galovcova M. Bruthans J. Filipovsky J. Laurent S. Cıfkova R. Lower-extremity arterial stiffness vs. aortic stiffness in the general population.Hypertens. Res. 2013; 36: 718-724https://doi.org/10.1038/hr.2013.21Crossref PubMed Scopus (31) Google Scholar]. The only traditional risk factor positively associated with faPWV was arterial hypertension [[16]Wohlfahrt P. Krajčoviechova A. Seidlerova J. Galovcova M. Bruthans J. Filipovsky J. Laurent S. Cıfkova R. Lower-extremity arterial stiffness vs. aortic stiffness in the general population.Hypertens. Res. 2013; 36: 718-724https://doi.org/10.1038/hr.2013.21Crossref PubMed Scopus (31) Google Scholar]. Lower limb PWV was reduced in patients with peripheral arterial disease who had either low ABI or high ABI [[16]Wohlfahrt P. Krajčoviechova A. Seidlerova J. Galovcova M. Bruthans J. Filipovsky J. Laurent S. Cıfkova R. Lower-extremity arterial stiffness vs. aortic stiffness in the general population.Hypertens. Res. 2013; 36: 718-724https://doi.org/10.1038/hr.2013.21Crossref PubMed Scopus (31) Google Scholar]. Low ABI is the result of stenotic or obstructive atherosclerotic plaques that lower blood pressure in the artery and consequently spuriously decrease the PWV. Somewhat intriguingly, increased ABI did not translate into high faPWV [[16]Wohlfahrt P. Krajčoviechova A. Seidlerova J. Galovcova M. Bruthans J. Filipovsky J. Laurent S. Cıfkova R. Lower-extremity arterial stiffness vs. aortic stiffness in the general population.Hypertens. Res. 2013; 36: 718-724https://doi.org/10.1038/hr.2013.21Crossref PubMed Scopus (31) Google Scholar], which indicates that the internal distending pressure of lower extremity arteries (which drives the pulse wave propagation) is not necessarily mirrored by the externally measured blood pressure [[15]Schillaci G. Pucci G. Lower-limb pulse wave velocity: correlations and clinical value.Hypertens. Res. 2013; 36: 679-681https://doi.org/10.1038/hr.2013.47Crossref PubMed Scopus (3) Google Scholar]. No association was found between traditional risk factors for atherosclerosis and faPWV - with the exception of positive correlation with arterial hypertension - in the post Monica Study [[16]Wohlfahrt P. Krajčoviechova A. Seidlerova J. Galovcova M. Bruthans J. Filipovsky J. Laurent S. Cıfkova R. Lower-extremity arterial stiffness vs. aortic stiffness in the general population.Hypertens. Res. 2013; 36: 718-724https://doi.org/10.1038/hr.2013.21Crossref PubMed Scopus (31) Google Scholar], while the ARIC study found a small inverse relationship of faPWV with smoking and prevalent CVD, and a small positive correlation with age, systolic blood pressure and HDL-cholesterol [[1]Stone K. Fryer S. Faulkner J. Hughes T.M. Tanaka H. Stoner L. et al.Associations of lower-limb atherosclerosis and arteriosclerosis with cardiovascular risk factors and disease in older adults: the atherosclerosis risk in communities (ARIC) study.Atherosclerosis. 2021; https://doi.org/10.1016/j.atherosclerosis.2021.10.014Abstract Full Text Full Text PDF Scopus (1) Google Scholar], somewhat similar to three other studies [17Liu S. Kim E.D. Wu A. Meyer M.L. Cheng S. Hoogeveen R.C. et al.Central and peripheral pulse wave velocity and subclinical myocardial stress and damage in older adults.PLoS One. 2019; 14e0212892https://doi.org/10.1371/journal.pone.0212892Crossref PubMed Scopus (8) Google Scholar, 18Hatsuda S. Shoji T. Shinohara K. Kimoto E. Mori K. Fukumoto S. et al.Regional arterial stiffness associated with ischemic heart disease in type 2 diabetes mellitus.J. Atherosclerosis Thromb. 2006; 13: 114-121https://doi.org/10.5551/jat.13.114Crossref PubMed Scopus (51) Google Scholar, 19Tsuchikura S. Shoji T. Kimoto E. Shinohara K. Hatsuda S. Koyama H. et al.Central versus peripheral arterial stiffness in association with coronary, cerebral and peripheral arterial disease.Atherosclerosis. 2010; 211: 480-485https://doi.org/10.1016/j.atherosclerosis.2010.03.037Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar]. One of these reports was from the same ARIC study cohort [[17]Liu S. Kim E.D. Wu A. Meyer M.L. Cheng S. Hoogeveen R.C. et al.Central and peripheral pulse wave velocity and subclinical myocardial stress and damage in older adults.PLoS One. 2019; 14e0212892https://doi.org/10.1371/journal.pone.0212892Crossref PubMed Scopus (8) Google Scholar], while the study of Hatsuda et al. found only a small, insignificant negative correlation between non-HDL-cholesterol and faPWV [[18]Hatsuda S. Shoji T. Shinohara K. Kimoto E. Mori K. Fukumoto S. et al.Regional arterial stiffness associated with ischemic heart disease in type 2 diabetes mellitus.J. Atherosclerosis Thromb. 2006; 13: 114-121https://doi.org/10.5551/jat.13.114Crossref PubMed Scopus (51) Google Scholar]. On the other hand, the study of Tsuchikura et al. reported on a significant negative association between faPWV and coronary disease [[19]Tsuchikura S. Shoji T. Kimoto E. Shinohara K. Hatsuda S. Koyama H. et al.Central versus peripheral arterial stiffness in association with coronary, cerebral and peripheral arterial disease.Atherosclerosis. 2010; 211: 480-485https://doi.org/10.1016/j.atherosclerosis.2010.03.037Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar]. A meta-analysis of 9 studies that recorded cardiovascular outcomes in relation to ABI found a high specificity of low ABI for increased cardiovascular risk, but a low sensitivity for substantially increased risk of coronary disease, stroke or increased mortality [[20]Doobay A.V. Anand S.S. Sensitivity and specificity of the ankle-brachial index to predict future cardiovascular outcomes: a systematic review.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1463-1469https://doi.org/10.1161/01.ATV.0000168911.78624.b7Crossref PubMed Scopus (277) Google Scholar]. The main reason for the low sensitivity of low ABI is that advanced atherosclerosis may be present in various vascular beds before plaques become flow-limiting in the lower limb arteries. In other words, a low ABI helps to “rule in” a high-risk patient, but a normal ABI does not “rule out” a high-risk patient. Cardiovascular mortality and total mortality increase also with high ABI above 1.4, which implies incompressible arteries, usually due to mediocalcinosis in the context of diabetes or kidney disease [[21]Resnick H.E. Lindsay R.S. McDermott M.M. Devereux R.B. Jones K.L. Fabsitz R.R. et al.Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study.Circulation. 2004; 109: 733-739https://doi.org/10.1161/01.CIR.0000112642.63927.54Crossref PubMed Scopus (726) Google Scholar]. In summary, while ABI may impact on the management of an individual patient when values are abnormal (<0.9 or >1.4), it is too early to base clinical decisions on values of faPWV. In spite of the simplicity of obtaining faPWV by automated oscillometric screening devices, faPWV should at present remain the subject of epidemiological research, and prospective studies correlating faPWV with clinical outcomes are eagerly awaited. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.