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Is increased arterial stiffness a cause or consequence of atherosclerosis?

  • Laura Hansen
    Affiliations
    Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, USA
    Search for articles by this author
  • W. Robert Taylor
    Correspondence
    Corresponding author. 101 Woodruff Circle, Suite 319 WMB, Atlanta, GA 30322, USA.
    Affiliations
    Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, USA

    Division of Cardiology, Atlanta Veterans Affairs Medical Center, Decatur, GA, USA

    The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
    Search for articles by this author
Published:April 20, 2016DOI:https://doi.org/10.1016/j.atherosclerosis.2016.04.014
Is increased arterial stiffness a cause or consequence of atherosclerosis?
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      Decreased vascular compliance of the large arteries manifests as increased arterial pulse pressure with both higher systolic pressures and lower diastolic pressures without a significant change in mean pressure. The clinical consequences of higher systolic pressure include an increased risk of stroke and myocardial infarction. Our understanding of changes in vascular mechanics and its effect on blood pressure has grown as technology has improved our ability to quantify vascular stiffness in man. Multiple studies have shown that arterial stiffness as determined by pulse wave velocity (PWV) can be used as a predictor for cardiovascular events [
      • Mitchell G.F.
      • Hwang S.J.
      • Vasan R.S.
      • Larson M.G.
      • Pencina M.J.
      • Hamburg N.M.
      • Vita J.A.
      • Levy D.
      • Benjamin E.J.
      Arterial stiffness and cardiovascular events: the Framingham Heart Study.
      Circulation. 2010; 121 (Epub 2010/01/20. PubMed PMID: 20083680; PMCID: Pmc2836717): 505-511https://doi.org/10.1161/circulationaha.109.886655
      ,
      • Willum-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 (Epub 2006/02/08. PubMed PMID: 16461839): 664-670https://doi.org/10.1161/circulationaha.105.579342
      ,
      • Jankowski P.
      • Kawecka-Jaszcz K.
      • Czarnecka D.
      • Brzozowska-Kiszka M.
      • Styczkiewicz K.
      • Loster M.
      • Kloch-Badełek M.
      • Wiliński J.
      • Curyło A.M.
      • Dudek D.
      Pressure obotAB, Group SS. Pulsatile but not steady component of blood pressure predicts cardiovascular events in coronary patients.
      Hypertension. 2008; 51: 848-855https://doi.org/10.1161/hypertensionaha.107.101725
      ,
      • Mattace-Raso F.U.S.
      • Van Der Cammen T.J.M.
      • Hofman A.
      • Van Popele N.M.
      • Bos M.L.
      • Schalekamp M.A.D.H.
      • Asmar R.
      • Reneman R.S.
      • Hoeks A.P.G.
      • Breteler M.M.B.
      • Witteman J.C.M.
      Arterial stiffness and risk of coronary heart disease and stroke: The Rotterdam Study.
      Circulation. 2006; 113: 657-663https://doi.org/10.1161/CIRCULATIONAHA.105.555235
      ,
      • Vlachopoulos C.
      • Aznaouridis K.
      • Stefanadis C.
      Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis.
      J. Am. Coll. Cardiol. 2010; 55 (Epub 2010/03/27. PubMed PMID: 20338492): 1318-1327https://doi.org/10.1016/j.jacc.2009.10.061
      ,
      • Blacher J.
      • Asmar R.
      • Djane S.
      • London G.M.
      • Safar M.E.
      Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients.
      Hypertension. 1999; 33: 1111-1117https://doi.org/10.1161/01.hyp.33.5.1111
      ,
      • Domanski M.
      • Norman J.
      • Wolz M.
      • Mitchell G.
      • Pfeffer M.
      Cardiovascular risk assessment using pulse pressure in the first national health and nutrition examination survey (NHANES I).
      Hypertension. 2001; 38: 793-797https://doi.org/10.1161/hy1001.092966
      ]. A meta-analysis of 17 studies using pulse wave velocity as a measure of arterial stiffness found that an increase in PWV by 1 m/s corresponded to a 14% increased risk of cardiovascular events and a 15% increase in mortality [
      • Vlachopoulos C.
      • Aznaouridis K.
      • Stefanadis C.
      Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis.
      J. Am. Coll. Cardiol. 2010; 55 (Epub 2010/03/27. PubMed PMID: 20338492): 1318-1327https://doi.org/10.1016/j.jacc.2009.10.061
      ]. Another study following the First National Health and Nutrition Examination Survey found that a pulse pressure increase of 10 mmHg was associated with an increased risk of cardiovascular death of 26% in people age 25–45 and 10% in people 46–77 years [
      • Domanski M.
      • Norman J.
      • Wolz M.
      • Mitchell G.
      • Pfeffer M.
      Cardiovascular risk assessment using pulse pressure in the first national health and nutrition examination survey (NHANES I).
      Hypertension. 2001; 38: 793-797https://doi.org/10.1161/hy1001.092966
      ]. Additional studies have specifically correlated increased arterial stiffness with atherosclerosis [
      • van Popele N.M.
      • Grobbee D.E.
      • Bots M.L.
      • Asmar R.
      • Topouchian J.
      • Reneman R.S.
      • Hoeks A.P.
      • van der Kuip D.A.
      • Hofman A.
      • Witteman J.C.
      Association between arterial stiffness and atherosclerosis. The Rotterdam Study.
      Stroke. 2001; 32: 454-460
      ,
      • Oberoi S.
      • Schoepf U.J.
      • Meyer M.
      • Henzler T.
      • Rowe G.W.
      • Costello P.
      • Nance J.W.
      Progression of arterial stiffness and coronary atherosclerosis: longitudinal evaluation by cardiac CT.
      AJR Am. J. Roentgenol. 2013; 200 (Epub 2013/03/26. PubMed PMID: 23521451): 798-804https://doi.org/10.2214/ajr.12.8653
      ,
      • Palombo C.
      • Kozakova M.
      Arterial stiffness, atherosclerosis and cardiovascular risk: Pathophysiologic mechanisms and emerging clinical indications.
      Vasc. Pharmacol. 2016; 77: 1-7https://doi.org/10.1016/j.vph.2015.11.083
      ].
      The positive correlation between these mechanical parameters and disease progression, in both animal and human studies support the concept that these mechanical and physical changes play an important causal role in the progression of atherosclerosis. Thus, in their paper in this issue of Atherosclerosis, Maedeker et al. specifically test this hypothesis using a mouse model which has both high blood pressure and decreased compliance due to a decrease in elastin content [
      • Maedeker J.A.
      • Stoka K.V.
      • Bhayani S.A.
      • Gardner W.S.
      • Bennett L.
      • Procknow J.D.
      • Staiculescu M.C.
      • Walji T.A.
      • Craft C.S.
      • Wagenseil J.E.
      Hypertension and decreased aortic compliance due to reduced elastin amounts do not increase atherosclerotic plaque accumulation in Ldlr-/- mice.
      Atherosclerosis. 2016; (in press)
      ]. Importantly, this model does not result in elastin fragmentation thus avoiding the potential off target effects of elastin fragments. Surprisingly and contrary to the authors' original hypothesis, these mice did not have increased plaque formation. While aortic compliance and ultrastructure differ significantly between mice and man (factors which may impact the applicability of the findings to humans) the overall negative results of the current study are nonetheless quite striking and may have very important implications for our understanding of the pathogenesis of atherosclerosis. These findings suggest that the relationship between atherosclerosis and decreased vascular compliance might not be as straightforward as previously proposed and that increased stiffness is not the cause of increased atherosclerosis but rather a consequence of the pathological changes in the atherosclerotic arterial wall.
      The hypothesis that increased stiffness and pulse pressure can lead to atherosclerosis is based on the concept that consequences of increased stiffness, including hemodynamic changes sensed by endothelial cells as well as strain changes that are sensed by smooth muscle cells, result in downstream signaling events that promote atherosclerosis [
      • Palombo C.
      • Kozakova M.
      Arterial stiffness, atherosclerosis and cardiovascular risk: Pathophysiologic mechanisms and emerging clinical indications.
      Vasc. Pharmacol. 2016; 77: 1-7https://doi.org/10.1016/j.vph.2015.11.083
      ,
      • Birukov K.G.
      Cyclic stretch, reactive oxygen species, and vascular remodeling.
      Antioxidants Redox Signal. 2009; 11 (Epub 2009/02/04. PubMed PMID: 19186986; PMCID: Pmc2842585): 1651-1667https://doi.org/10.1089/ars.2008.2390
      ]. Vascular cell dysfunction, specifically dysregulation of nitric oxide and smooth muscle cell phenotypic switching to a more synthetic, proliferative, migratory, and inflammatory phenotype, are important cellular changes in the development of atherosclerotic plaques [
      • Bennett M.R.
      • Sinha S.
      • Owens G.K.
      Vascular Smooth Muscle Cells in Atherosclerosis.
      Circulation Res. 2016; 118: 692-702https://doi.org/10.1161/circresaha.115.306361
      ,
      • Owens G.K.
      • Kumar M.S.
      • Wamhoff B.R.
      Molecular regulation of vascular smooth muscle cell differentiation in development and disease.
      Physiol. Rev. 2004; 84: 767-801https://doi.org/10.1152/physrev.00041.2003
      ,
      • Davignon J.
      • Ganz P.
      Role of endothelial dysfunction in atherosclerosis.
      Circulation. 2004; 109: III-27-III-32https://doi.org/10.1161/01.CIR.0000131515.03336.f8
      ,
      • Chatzizisis Y.S.
      • Coskun A.U.
      • Jonas M.
      • Edelman E.R.
      • Feldman C.L.
      • Stone P.H.
      Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior.
      J. Am. Coll. Cardiol. 2007; 49 (Epub 2007/06/30. PubMed PMID: 17599600): 2379-2393https://doi.org/10.1016/j.jacc.2007.02.059
      ]. However, the mechanisms controlling these pathological changes in phenotype and cellular signaling are not completely understood. The results of this study seem to indicate that the changes in the local mechanical environment may not be a predominant factor in driving atherogenesis, or that other changes in cell signaling, cell attachment, or the extracellular matrix may account for the different degrees of plaque development despite similar vascular mechanical changes. Indeed, the authors suggest that further insults to the vasculature such as elastin fragmentation might be necessary for plaque formation and that changes in stiffness alone are not enough to promote the development of atherosclerosis. This hypothesis is supported by comparing the current paper with a similar one by Van Herck et al. which looked at atherosclerotic plaque development in ApoE−/−C1039G ± which have a mutation in the fibrillin-1 gene that causes elastin fragmentation in addition to increased aortic stiffness and increased pulse pressure [
      • Van Herck J.L.
      • De Meyer G.R.Y.
      • Martinet W.
      • Van Hove C.E.
      • Foubert K.
      • Theunis M.H.
      • Apers S.
      • Bult H.
      • Vrints C.J.
      • Herman A.G.
      Impaired fibrillin-1 function promotes features of plaque instability in apolipoprotein E–deficient mice.
      Circulation. 2009; 120: 2478-2487https://doi.org/10.1161/circulationaha.109.872663
      ]. The increased plaque formation in ApoE−/− C1039G± mice but not the ELN± Ldlr−/− mice in the study by Maedeker et al. suggest that the elastin fragmentation and observed increases in TGBβ are vital for the development of atherosclerosis in the first model. The paper by Van Herck et al. also demonstrated a further increase in both pulse pressure and aortic stiffness at 20 weeks versus 10 weeks on the Western diet, which also supports the hypothesis that these changes are the result of atherosclerosis development as opposed to a cause of it.
      The findings in the current study by Maedeker et al. are important because they suggest a paradigm shift in the way we think about the development of atherosclerosis and strategies for better treatment. Currently, the focus on vascular stiffness as a causative factor in atherosclerosis has led to studies which attempt to modulate vascular stiffness with the expectation that it will have beneficial effects in preventing or slowing disease progression. These interventions include more global approaches including lifestyle changes (weight loss, smoking cessation, etc.), dietary supplements (fish oil, soy isoflavones, etc.), and pharmaceutical control of blood pressure [
      • Wu C.F.
      • Liu P.Y.
      • Wu T.J.
      • Hung Y.
      • Yang S.P.
      • Lin G.M.
      Therapeutic modification of arterial stiffness: An update and comprehensive review.
      World J. Cardiol. 2015; 7 (Epub 2015/12/05. PubMed PMID: 26635922; PMCID: Pmc4660469): 742-753https://doi.org/10.4330/wjc.v7.i11.742
      ]. Other approaches to restore vascular compliance are more specific and include using small molecules to block or break advanced glycation end products (AGEs), disrupt collagen cross-links, or inhibit metalloproteinase activity to reduce elastin fragmentation [
      • Wolffenbuttel B.H.
      • Boulanger C.M.
      • Crijns F.R.
      • Huijberts M.S.
      • Poitevin P.
      • Swennen G.N.
      • Vasan S.
      • Egan J.J.
      • Ulrich P.
      • Cerami A.
      • Levy B.I.
      Breakers of advanced glycation end products restore large artery properties in experimental diabetes.
      Proc. Natl. Acad. Sci. U. S. A. 1998; 95 (Epub 1998/05/16. PubMed PMID: 9539789; PMCID: Pmc22541): 4630-4634
      ,
      • Cheng G.
      • Wang L.L.
      • Long L.
      • Liu H.Y.
      • Cui H.
      • Qu W.S.
      • Li S.
      Beneficial effects of C36, a novel breaker of advanced glycation end products cross-links, on the cardiovascular system of diabetic rats.
      Br. J. Pharmacol. 2007; 152 (Epub 2007/10/30. PubMed PMID: 17965740; PMCID: Pmc2189992): 1196-1206https://doi.org/10.1038/sj.bjp.0707533
      ,
      • Smulyan H.
      • Mookherjee S.
      • Safar M.E.
      The two faces of hypertension: role of aortic stiffness.
      J. Am. Soc. Hypertens. 2016; 10: 175-183https://doi.org/10.1016/j.jash.2015.11.012
      ,
      • Kass D.A.
      • Shapiro E.P.
      • Kawaguchi M.
      • Capriotti A.R.
      • Scuteri A.
      • deGroof R.C.
      • Lakatta E.G.
      Improved arterial compliance by a novel advanced glycation end-product crosslink breaker.
      Circulation. 2001; 104 (Epub 2001/09/26. PubMed PMID: 11571237): 1464-1470
      ,
      • Wang M.
      • Zhang J.
      • Telljohann R.
      • Jiang L.
      • Wu J.
      • Monticone R.E.
      • Kapoor K.
      • Talan M.
      • Lakatta E.G.
      Chronic matrix metalloproteinase inhibition retards age-associated arterial proinflammation and increase in blood pressure.
      Hypertension. 2012; 60 (Epub 2012/06/13. PubMed PMID: 22689745; PMCID: Pmc3537179): 459-466https://doi.org/10.1161/hypertensionaha.112.191270
      ]. While these studies have shown some changes in vascular compliance, the findings in the paper by Maedeker et al. raise questions as to the effectiveness of these approaches that focus specifically on improving wall compliance as it suggests vascular stiffness alone may not be an important factor in disease progression. Indeed, increased vascular stiffness may simply be a consequence of the pathological changes that occur in the arterial wall during the progression of atherosclerosis.

      Financial support

      Supported in part by NHLBI F32HL 124974 (L.H.)

      References

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        • Hwang S.J.
        • Vasan R.S.
        • Larson M.G.
        • Pencina M.J.
        • Hamburg N.M.
        • Vita J.A.
        • Levy D.
        • Benjamin E.J.
        Arterial stiffness and cardiovascular events: the Framingham Heart Study.
        Circulation. 2010; 121 (Epub 2010/01/20. PubMed PMID: 20083680; PMCID: Pmc2836717): 505-511https://doi.org/10.1161/circulationaha.109.886655
        View in Article
        • Willum-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 (Epub 2006/02/08. PubMed PMID: 16461839): 664-670https://doi.org/10.1161/circulationaha.105.579342
        View in Article
        • Jankowski P.
        • Kawecka-Jaszcz K.
        • Czarnecka D.
        • Brzozowska-Kiszka M.
        • Styczkiewicz K.
        • Loster M.
        • Kloch-Badełek M.
        • Wiliński J.
        • Curyło A.M.
        • Dudek D.
        Pressure obotAB, Group SS. Pulsatile but not steady component of blood pressure predicts cardiovascular events in coronary patients.
        Hypertension. 2008; 51: 848-855https://doi.org/10.1161/hypertensionaha.107.101725
        View in Article
        • Mattace-Raso F.U.S.
        • Van Der Cammen T.J.M.
        • Hofman A.
        • Van Popele N.M.
        • Bos M.L.
        • Schalekamp M.A.D.H.
        • Asmar R.
        • Reneman R.S.
        • Hoeks A.P.G.
        • Breteler M.M.B.
        • Witteman J.C.M.
        Arterial stiffness and risk of coronary heart disease and stroke: The Rotterdam Study.
        Circulation. 2006; 113: 657-663https://doi.org/10.1161/CIRCULATIONAHA.105.555235
        View in Article
        • Vlachopoulos C.
        • Aznaouridis K.
        • Stefanadis C.
        Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis.
        J. Am. Coll. Cardiol. 2010; 55 (Epub 2010/03/27. PubMed PMID: 20338492): 1318-1327https://doi.org/10.1016/j.jacc.2009.10.061
        View in Article
        • Blacher J.
        • Asmar R.
        • Djane S.
        • London G.M.
        • Safar M.E.
        Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients.
        Hypertension. 1999; 33: 1111-1117https://doi.org/10.1161/01.hyp.33.5.1111
        View in Article
        • Domanski M.
        • Norman J.
        • Wolz M.
        • Mitchell G.
        • Pfeffer M.
        Cardiovascular risk assessment using pulse pressure in the first national health and nutrition examination survey (NHANES I).
        Hypertension. 2001; 38: 793-797https://doi.org/10.1161/hy1001.092966
        View in Article
        • van Popele N.M.
        • Grobbee D.E.
        • Bots M.L.
        • Asmar R.
        • Topouchian J.
        • Reneman R.S.
        • Hoeks A.P.
        • van der Kuip D.A.
        • Hofman A.
        • Witteman J.C.
        Association between arterial stiffness and atherosclerosis. The Rotterdam Study.
        Stroke. 2001; 32: 454-460
        View in Article
        • Oberoi S.
        • Schoepf U.J.
        • Meyer M.
        • Henzler T.
        • Rowe G.W.
        • Costello P.
        • Nance J.W.
        Progression of arterial stiffness and coronary atherosclerosis: longitudinal evaluation by cardiac CT.
        AJR Am. J. Roentgenol. 2013; 200 (Epub 2013/03/26. PubMed PMID: 23521451): 798-804https://doi.org/10.2214/ajr.12.8653
        View in Article
        • Palombo C.
        • Kozakova M.
        Arterial stiffness, atherosclerosis and cardiovascular risk: Pathophysiologic mechanisms and emerging clinical indications.
        Vasc. Pharmacol. 2016; 77: 1-7https://doi.org/10.1016/j.vph.2015.11.083
        View in Article
        • Maedeker J.A.
        • Stoka K.V.
        • Bhayani S.A.
        • Gardner W.S.
        • Bennett L.
        • Procknow J.D.
        • Staiculescu M.C.
        • Walji T.A.
        • Craft C.S.
        • Wagenseil J.E.
        Hypertension and decreased aortic compliance due to reduced elastin amounts do not increase atherosclerotic plaque accumulation in Ldlr-/- mice.
        Atherosclerosis. 2016; (in press)
        View in Article
        • Birukov K.G.
        Cyclic stretch, reactive oxygen species, and vascular remodeling.
        Antioxidants Redox Signal. 2009; 11 (Epub 2009/02/04. PubMed PMID: 19186986; PMCID: Pmc2842585): 1651-1667https://doi.org/10.1089/ars.2008.2390
        View in Article
        • Bennett M.R.
        • Sinha S.
        • Owens G.K.
        Vascular Smooth Muscle Cells in Atherosclerosis.
        Circulation Res. 2016; 118: 692-702https://doi.org/10.1161/circresaha.115.306361
        View in Article
        • Owens G.K.
        • Kumar M.S.
        • Wamhoff B.R.
        Molecular regulation of vascular smooth muscle cell differentiation in development and disease.
        Physiol. Rev. 2004; 84: 767-801https://doi.org/10.1152/physrev.00041.2003
        View in Article
        • Davignon J.
        • Ganz P.
        Role of endothelial dysfunction in atherosclerosis.
        Circulation. 2004; 109: III-27-III-32https://doi.org/10.1161/01.CIR.0000131515.03336.f8
        View in Article
        • Chatzizisis Y.S.
        • Coskun A.U.
        • Jonas M.
        • Edelman E.R.
        • Feldman C.L.
        • Stone P.H.
        Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior.
        J. Am. Coll. Cardiol. 2007; 49 (Epub 2007/06/30. PubMed PMID: 17599600): 2379-2393https://doi.org/10.1016/j.jacc.2007.02.059
        View in Article
        • Van Herck J.L.
        • De Meyer G.R.Y.
        • Martinet W.
        • Van Hove C.E.
        • Foubert K.
        • Theunis M.H.
        • Apers S.
        • Bult H.
        • Vrints C.J.
        • Herman A.G.
        Impaired fibrillin-1 function promotes features of plaque instability in apolipoprotein E–deficient mice.
        Circulation. 2009; 120: 2478-2487https://doi.org/10.1161/circulationaha.109.872663
        View in Article
        • Wu C.F.
        • Liu P.Y.
        • Wu T.J.
        • Hung Y.
        • Yang S.P.
        • Lin G.M.
        Therapeutic modification of arterial stiffness: An update and comprehensive review.
        World J. Cardiol. 2015; 7 (Epub 2015/12/05. PubMed PMID: 26635922; PMCID: Pmc4660469): 742-753https://doi.org/10.4330/wjc.v7.i11.742
        View in Article
        • Wolffenbuttel B.H.
        • Boulanger C.M.
        • Crijns F.R.
        • Huijberts M.S.
        • Poitevin P.
        • Swennen G.N.
        • Vasan S.
        • Egan J.J.
        • Ulrich P.
        • Cerami A.
        • Levy B.I.
        Breakers of advanced glycation end products restore large artery properties in experimental diabetes.
        Proc. Natl. Acad. Sci. U. S. A. 1998; 95 (Epub 1998/05/16. PubMed PMID: 9539789; PMCID: Pmc22541): 4630-4634
        View in Article
        • Cheng G.
        • Wang L.L.
        • Long L.
        • Liu H.Y.
        • Cui H.
        • Qu W.S.
        • Li S.
        Beneficial effects of C36, a novel breaker of advanced glycation end products cross-links, on the cardiovascular system of diabetic rats.
        Br. J. Pharmacol. 2007; 152 (Epub 2007/10/30. PubMed PMID: 17965740; PMCID: Pmc2189992): 1196-1206https://doi.org/10.1038/sj.bjp.0707533
        View in Article
        • Smulyan H.
        • Mookherjee S.
        • Safar M.E.
        The two faces of hypertension: role of aortic stiffness.
        J. Am. Soc. Hypertens. 2016; 10: 175-183https://doi.org/10.1016/j.jash.2015.11.012
        View in Article
        • Kass D.A.
        • Shapiro E.P.
        • Kawaguchi M.
        • Capriotti A.R.
        • Scuteri A.
        • deGroof R.C.
        • Lakatta E.G.
        Improved arterial compliance by a novel advanced glycation end-product crosslink breaker.
        Circulation. 2001; 104 (Epub 2001/09/26. PubMed PMID: 11571237): 1464-1470
        View in Article
        • Wang M.
        • Zhang J.
        • Telljohann R.
        • Jiang L.
        • Wu J.
        • Monticone R.E.
        • Kapoor K.
        • Talan M.
        • Lakatta E.G.
        Chronic matrix metalloproteinase inhibition retards age-associated arterial proinflammation and increase in blood pressure.
        Hypertension. 2012; 60 (Epub 2012/06/13. PubMed PMID: 22689745; PMCID: Pmc3537179): 459-466https://doi.org/10.1161/hypertensionaha.112.191270
        View in Article

      Article info

      Publication history

      Published online: April 20, 2016
      Accepted: April 19, 2016
      Received: April 8, 2016

      Identification

      DOI: https://doi.org/10.1016/j.atherosclerosis.2016.04.014

      Copyright

      © 2016 Elsevier Ireland Ltd. All rights reserved.

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