EDITORIAL
Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp
Inside Out, Outside in – Vasa Vasorum and Coronary Spasm – Takao Shimohama, MD; Junya Ako, MD
B
ecause of the substantial reduction in restenosis, drugeluting stents (DES) have been rapidly accepted and integrated into daily clinical practice. However, DES are associated with several adverse clinical events, including very late stent thrombosis and coronary hyperconstriction.1 Endothelial injury is thought to be involved in coronary hyperconstriction (ie, abnormal vascular spasm after DES implantation).1,2 In a previous study using angioscopy, coronary endothelial dysfunction distal to stenting was associated with poor neointimal coverage after DES implantation.3 In search of the pathophysiology of this phenomenon, the clinical and experimental focus has been mainly on the endothelium, or what was happening inside the arteries.
Article p 1787 Large vessels, including the coronary arteries, have their own vascular system within the adventitia in the form of network of small vessels, which are called the vasa vasorum. Under physiological conditions, the vasa vasorum transport blood cells, nourishment, oxygen, and various molecules to the adventitia. Recently, the role of the vasa vasorum in the development of atherosclerosis has been receiving consider-
able attention and the vasa vasorum have been reported to be involved in vascular inflammation,4 atherosclerotic plaque formation via microvessel hemorrhage or microvessel leakage,5–7 and neointimal formation after mechanical vascular injury.8 An autopsy study found that an increase in intraplaque microvessel density was associated with plaque hemorrhage, a characteristic of unstable plaque (Table).9 In this issue of the Journal, Nishimiya et al10 report on their study to determine the association between vasa vasorum formation and coronary vasospasm after DES implantation. In this remarkably well-structured experimental study with 18 pigs, the authors found significantly increased coronary vasoconstriction in response to serotonin in sirolimus-eluting stent (SES) as compared with that in biolimus-eluting stents (BES). Vasa vasorum formation was more prominent with SES than with BES. Furthermore, macrophage infiltration in the adventitia and Rho-kinase expression, which presumably contributed to vasoconstriction, were enhanced in the SES group. Histologic analyses showed that there were more inflammatory changes and thrombus formation at SES edges as compared with BES. Vasoconstriction and macrophage density in the adventitia showed a positive correlation. Taken together, pathologic changes in the adventitia may play an important
Table. “Outside-in” Pathological Involvement in Various Clinical Conditions Year
Species
Artery
n
Diagnostic modality
Microvessel density
Findings
Kockx et al5
2003
Human
Carotid
15
Histology
NA
Focal intraplaque microhemorrhage
Kolodgie et al6
2003
Human
Coronary
24
Histology
NA
Intraplaque hemorrhage
Sluimer et al7
2009
Human
Coronary
28
Histology
Increased MV density
Microvascular leakage
2006
Swine
Coronary
40
Micro CT IVUS Histology
Increased MV after stenting
MV correlates to restenosis
2014
Human
Coronary
167
OCT
NA
NV correlates to neoatherosclerosis
2015
Swine
Coronary
18
Micro CT Histology
Increased MV after DES
Involvement of Rho-kinase
Author Plaque instability
Restenosis Cheema et al8 Neoatherosclerosis Tian et al15 Coronary spasm Nishimiya et al14
CT, computed tomography; DES, drug-eluting stent; IVUS, intravascular ultrasound; MV, microvessel; NA, not assessed; NV, neovascularization; OCT, optical coherence tomography.
The opinions expressed in this article are not necessarily those of the editors or of the Japanese Circulation Society. Received June 23, 2015; accepted June 23, 2015; released online July 8, 2015 Cardiovascular Medicine, Kitasato University, Sagamihara, Japan Mailing address: Junya Ako, MD, Cardiovascular Medicine, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara 252-0374, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-15-0698 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.79, August 2015
1694
SHIMOHAMA T et al.
role in abnormal vascular spasm after DES implantation. This is the first report to elucidate the involvement of adventitial vasa vasorum in abnormal vasoconstriction after DES implantation. In this detailed study using multiple modalities, including angiography, micro computed tomography (CT), and histological analysis, the authors demonstrated significant involvement of the vasa vasorum and Rho-kinase in this disorder. Clinical studies have shown that DES, especially first-generation DES, are associated with late target vessel revascularization and sudden death, for which this abnormal vascular reaction may at least in part be responsible. In that regard, this study’s results have clinical relevance in this era when DES are predominant in daily practice. The authors also show a significant difference between SES and BES, which is in line with the clinical finding that SES was associated with more clinically evident abnormal vascular reaction.2 The different polymers (durable polymer for SES and biodegradable polymer for BES) may account for the difference in the vascular reaction between the 2 types of DES. Considering that the drugs are likely to be fully released by the time of follow-up, polymers would play a critical role. However, it should be noted that less abnormal vascular reactions are reported with a current-generation DES using a durable polymer.11 Therefore, the difference may lie not in durable vs. biodegradable, but rather in the specific formulation of each polymer. Further studies are required to elucidate the exact mechanism that causes these untoward reactions in the adventitia. With an increasing clinical interest in adventitial vasa vasorum, it is of great importance to assess this vasculature quantitatively as well as qualitatively. In addition to noninvasive imaging modalities such as multidetector coronary CT and magnetic resonance imaging, future in-vivo imaging modalities may include intravascular ultrasound with contrast injection,12 and optical coherence tomography, the accuracy of which for the evaluation of adventitial vasa vasorum formation has been validated in pigs and humans.13,14 We have only become aware that atherosclerotic disease is not a process confined to the intima, but rather a dynamic interaction with the surrounding environment. Recent recognition of neovascularization within the neointima15 may be another reminder that we have to look deeper than the luminal surface. More studies will further clarify the relevance of the “outside-in” process in vascular diseases. Disclosures J.A. received research funding from Kissei, Astellas, Mediphysics, Ono, Bristle Meyers, Pfizer, Behringer Ingelheim, Kyowa Kirin, Bayer, Daiichi-Sankyo, Eisai, Teijin, Kowa, Mochida, Abbott Vascular, Asahi Intec, Astra Zeneca, Dainippon Sumitomo, Otsuka, Tanabe Mitsubishi, Takeda, Japan Lifeline, and lecture fees from Actelion, Sanofi, TanabeMitsubishi, Takeda, Mochida, Shionogi, Kaneka, Astra-Zeneca, Astellas, Volcano, Terumo, Eisai, Bristle-Meyers, St. Jude Medical, Kyowa-Kirin,
Pfizer, Ono Pharmaceutical, Abbott Vascular, Toa Eiyo, JIMRO, Kissei, Dainippon Sumitomo.
References 1. Togni M, Windecker S, Cocchia R, Wenaweser P, Cook S, Billinger M, et al. Sirolimus-eluting stents associated with paradoxic coronary vasoconstriction. J Am Coll Cardiol 2005; 46: 231 – 236. 2. Hamilos MI, Ostojic M, Beleslin B, Sagic D, Mangovski L, Stojkovic S, et al. Differential effects of drug-eluting stents on local endothelium-dependent coronary vasomotion. J Am Coll Cardiol 2008; 51: 2123 – 2129. 3. Mitsutake Y, Ueno T, Yokoyama S, Sasaki K, Sugi Y, Toyama Y, et al. Coronary endothelial dysfunction distal to stent of first-generation drug-eluting stents. JACC Cardiovasc Interv 2012; 5: 966 – 973. 4. Maiellaro K, Taylor WR. The role of the adventitia in vascular inflammation. Cardiovasc Res 2007; 75: 640 – 648. 5. Kockx MM, Cromheeke KM, Knaapen MW, Bosmans JM, De Meyer GR, Herman AG, et al. Phagocytosis and macrophage activation associated with hemorrhagic microvessels in human atherosclerosis. Arterioscler Thromb Vasc Biol 2003; 23: 440 – 446. 6. Kolodgie FD, Gold HK, Burke AP, Fowler DR, Kruth HS, Weber DK, et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003; 349: 2316 – 2325. 7. Sluimer JC, Kolodgie FD, Bijnens AP, Maxfield K, Pacheco E, Kutys B, et al. Thin-walled microvessels in human coronary atherosclerotic plaques show incomplete endothelial junctions relevance of compromised structural integrity for intraplaque microvascular leakage. J Am Coll Cardiol 2009; 53: 1517 – 1527. 8. Cheema AN, Hong T, Nili N, Segev A, Moffat JG, Lipson KE, et al. Adventitial microvessel formation after coronary stenting and the effects of SU11218, a tyrosine kinase inhibitor. J Am Coll Cardiol 2006; 47: 1067 – 1075. 9. Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, et al. Atherosclerotic plaque progression and vulnerability to rupture: Angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 2005; 25: 2054 – 2061. 10. Nishimiya K, Matsumoto Y, Shindo T, Hanawa K, Hasebe Y, Tsuburaya R, et al. Association of adventitial vasa vasorum and inflammation with coronary hyperconstriction after drug-eluting stent implantation in pigs in vivo. Circ J 2015; 79: 1787 – 1798. 11. Nakazawa G, Shinke T, Ijichi T, Matsumoto D, Otake H, Torii S, et al. Comparison of vascular response between durable and biodegradable polymer-based drug-eluting stents in a porcine coronary artery model. EuroIntervention 2014; 10: 717 – 723. 12. Staub D, Patel MB, Tibrewala A, Ludden D, Johnson M, Espinosa P, et al. Vasa vasorum and plaque neovascularization on contrastenhanced carotid ultrasound imaging correlates with cardiovascular disease and past cardiovascular events. Stroke 2010; 41: 41 – 47. 13. Nishimiya K, Matsumoto Y, Takahashi J, Uzuka H, Odaka Y, Nihei T, et al. In vivo visualization of adventitial vasa vasorum of the human coronary artery on optical frequency domain imaging: Validation study. Circ J 2014; 78: 2516 – 2518. 14. Nishimiya K, Matsumoto Y, Uzuka H, Oyama K, Tanaka A, Taruya A, et al. Accuracy of optical frequency domain imaging for evaluation of coronary adventitial vasa vasorum formation after stent implantation in pigs and humans: A validation study. Circ J 2015; 79: 1323 – 1331. 15. Tian J, Ren X, Uemura S, Dauerman H, Prasad A, Toma C, et al. Spatial heterogeneity of neoatherosclerosis and its relationship with neovascularization and adjacent plaque characteristics: Optical coherence tomography study. Am Heart J 2014; 167: 884 – 892.e2, doi:10.1016/j.ahj.2014.03.013.
Circulation Journal Vol.79, August 2015
Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp
Inside Out, Outside in – Vasa Vasorum and Coronary Spasm – Takao Shimohama, MD; Junya Ako, MD
B
ecause of the substantial reduction in restenosis, drugeluting stents (DES) have been rapidly accepted and integrated into daily clinical practice. However, DES are associated with several adverse clinical events, including very late stent thrombosis and coronary hyperconstriction.1 Endothelial injury is thought to be involved in coronary hyperconstriction (ie, abnormal vascular spasm after DES implantation).1,2 In a previous study using angioscopy, coronary endothelial dysfunction distal to stenting was associated with poor neointimal coverage after DES implantation.3 In search of the pathophysiology of this phenomenon, the clinical and experimental focus has been mainly on the endothelium, or what was happening inside the arteries.
Article p 1787 Large vessels, including the coronary arteries, have their own vascular system within the adventitia in the form of network of small vessels, which are called the vasa vasorum. Under physiological conditions, the vasa vasorum transport blood cells, nourishment, oxygen, and various molecules to the adventitia. Recently, the role of the vasa vasorum in the development of atherosclerosis has been receiving consider-
able attention and the vasa vasorum have been reported to be involved in vascular inflammation,4 atherosclerotic plaque formation via microvessel hemorrhage or microvessel leakage,5–7 and neointimal formation after mechanical vascular injury.8 An autopsy study found that an increase in intraplaque microvessel density was associated with plaque hemorrhage, a characteristic of unstable plaque (Table).9 In this issue of the Journal, Nishimiya et al10 report on their study to determine the association between vasa vasorum formation and coronary vasospasm after DES implantation. In this remarkably well-structured experimental study with 18 pigs, the authors found significantly increased coronary vasoconstriction in response to serotonin in sirolimus-eluting stent (SES) as compared with that in biolimus-eluting stents (BES). Vasa vasorum formation was more prominent with SES than with BES. Furthermore, macrophage infiltration in the adventitia and Rho-kinase expression, which presumably contributed to vasoconstriction, were enhanced in the SES group. Histologic analyses showed that there were more inflammatory changes and thrombus formation at SES edges as compared with BES. Vasoconstriction and macrophage density in the adventitia showed a positive correlation. Taken together, pathologic changes in the adventitia may play an important
Table. “Outside-in” Pathological Involvement in Various Clinical Conditions Year
Species
Artery
n
Diagnostic modality
Microvessel density
Findings
Kockx et al5
2003
Human
Carotid
15
Histology
NA
Focal intraplaque microhemorrhage
Kolodgie et al6
2003
Human
Coronary
24
Histology
NA
Intraplaque hemorrhage
Sluimer et al7
2009
Human
Coronary
28
Histology
Increased MV density
Microvascular leakage
2006
Swine
Coronary
40
Micro CT IVUS Histology
Increased MV after stenting
MV correlates to restenosis
2014
Human
Coronary
167
OCT
NA
NV correlates to neoatherosclerosis
2015
Swine
Coronary
18
Micro CT Histology
Increased MV after DES
Involvement of Rho-kinase
Author Plaque instability
Restenosis Cheema et al8 Neoatherosclerosis Tian et al15 Coronary spasm Nishimiya et al14
CT, computed tomography; DES, drug-eluting stent; IVUS, intravascular ultrasound; MV, microvessel; NA, not assessed; NV, neovascularization; OCT, optical coherence tomography.
The opinions expressed in this article are not necessarily those of the editors or of the Japanese Circulation Society. Received June 23, 2015; accepted June 23, 2015; released online July 8, 2015 Cardiovascular Medicine, Kitasato University, Sagamihara, Japan Mailing address: Junya Ako, MD, Cardiovascular Medicine, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara 252-0374, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-15-0698 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Circulation Journal Vol.79, August 2015
1694
SHIMOHAMA T et al.
role in abnormal vascular spasm after DES implantation. This is the first report to elucidate the involvement of adventitial vasa vasorum in abnormal vasoconstriction after DES implantation. In this detailed study using multiple modalities, including angiography, micro computed tomography (CT), and histological analysis, the authors demonstrated significant involvement of the vasa vasorum and Rho-kinase in this disorder. Clinical studies have shown that DES, especially first-generation DES, are associated with late target vessel revascularization and sudden death, for which this abnormal vascular reaction may at least in part be responsible. In that regard, this study’s results have clinical relevance in this era when DES are predominant in daily practice. The authors also show a significant difference between SES and BES, which is in line with the clinical finding that SES was associated with more clinically evident abnormal vascular reaction.2 The different polymers (durable polymer for SES and biodegradable polymer for BES) may account for the difference in the vascular reaction between the 2 types of DES. Considering that the drugs are likely to be fully released by the time of follow-up, polymers would play a critical role. However, it should be noted that less abnormal vascular reactions are reported with a current-generation DES using a durable polymer.11 Therefore, the difference may lie not in durable vs. biodegradable, but rather in the specific formulation of each polymer. Further studies are required to elucidate the exact mechanism that causes these untoward reactions in the adventitia. With an increasing clinical interest in adventitial vasa vasorum, it is of great importance to assess this vasculature quantitatively as well as qualitatively. In addition to noninvasive imaging modalities such as multidetector coronary CT and magnetic resonance imaging, future in-vivo imaging modalities may include intravascular ultrasound with contrast injection,12 and optical coherence tomography, the accuracy of which for the evaluation of adventitial vasa vasorum formation has been validated in pigs and humans.13,14 We have only become aware that atherosclerotic disease is not a process confined to the intima, but rather a dynamic interaction with the surrounding environment. Recent recognition of neovascularization within the neointima15 may be another reminder that we have to look deeper than the luminal surface. More studies will further clarify the relevance of the “outside-in” process in vascular diseases. Disclosures J.A. received research funding from Kissei, Astellas, Mediphysics, Ono, Bristle Meyers, Pfizer, Behringer Ingelheim, Kyowa Kirin, Bayer, Daiichi-Sankyo, Eisai, Teijin, Kowa, Mochida, Abbott Vascular, Asahi Intec, Astra Zeneca, Dainippon Sumitomo, Otsuka, Tanabe Mitsubishi, Takeda, Japan Lifeline, and lecture fees from Actelion, Sanofi, TanabeMitsubishi, Takeda, Mochida, Shionogi, Kaneka, Astra-Zeneca, Astellas, Volcano, Terumo, Eisai, Bristle-Meyers, St. Jude Medical, Kyowa-Kirin,
Pfizer, Ono Pharmaceutical, Abbott Vascular, Toa Eiyo, JIMRO, Kissei, Dainippon Sumitomo.
References 1. Togni M, Windecker S, Cocchia R, Wenaweser P, Cook S, Billinger M, et al. Sirolimus-eluting stents associated with paradoxic coronary vasoconstriction. J Am Coll Cardiol 2005; 46: 231 – 236. 2. Hamilos MI, Ostojic M, Beleslin B, Sagic D, Mangovski L, Stojkovic S, et al. Differential effects of drug-eluting stents on local endothelium-dependent coronary vasomotion. J Am Coll Cardiol 2008; 51: 2123 – 2129. 3. Mitsutake Y, Ueno T, Yokoyama S, Sasaki K, Sugi Y, Toyama Y, et al. Coronary endothelial dysfunction distal to stent of first-generation drug-eluting stents. JACC Cardiovasc Interv 2012; 5: 966 – 973. 4. Maiellaro K, Taylor WR. The role of the adventitia in vascular inflammation. Cardiovasc Res 2007; 75: 640 – 648. 5. Kockx MM, Cromheeke KM, Knaapen MW, Bosmans JM, De Meyer GR, Herman AG, et al. Phagocytosis and macrophage activation associated with hemorrhagic microvessels in human atherosclerosis. Arterioscler Thromb Vasc Biol 2003; 23: 440 – 446. 6. Kolodgie FD, Gold HK, Burke AP, Fowler DR, Kruth HS, Weber DK, et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003; 349: 2316 – 2325. 7. Sluimer JC, Kolodgie FD, Bijnens AP, Maxfield K, Pacheco E, Kutys B, et al. Thin-walled microvessels in human coronary atherosclerotic plaques show incomplete endothelial junctions relevance of compromised structural integrity for intraplaque microvascular leakage. J Am Coll Cardiol 2009; 53: 1517 – 1527. 8. Cheema AN, Hong T, Nili N, Segev A, Moffat JG, Lipson KE, et al. Adventitial microvessel formation after coronary stenting and the effects of SU11218, a tyrosine kinase inhibitor. J Am Coll Cardiol 2006; 47: 1067 – 1075. 9. Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, et al. Atherosclerotic plaque progression and vulnerability to rupture: Angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 2005; 25: 2054 – 2061. 10. Nishimiya K, Matsumoto Y, Shindo T, Hanawa K, Hasebe Y, Tsuburaya R, et al. Association of adventitial vasa vasorum and inflammation with coronary hyperconstriction after drug-eluting stent implantation in pigs in vivo. Circ J 2015; 79: 1787 – 1798. 11. Nakazawa G, Shinke T, Ijichi T, Matsumoto D, Otake H, Torii S, et al. Comparison of vascular response between durable and biodegradable polymer-based drug-eluting stents in a porcine coronary artery model. EuroIntervention 2014; 10: 717 – 723. 12. Staub D, Patel MB, Tibrewala A, Ludden D, Johnson M, Espinosa P, et al. Vasa vasorum and plaque neovascularization on contrastenhanced carotid ultrasound imaging correlates with cardiovascular disease and past cardiovascular events. Stroke 2010; 41: 41 – 47. 13. Nishimiya K, Matsumoto Y, Takahashi J, Uzuka H, Odaka Y, Nihei T, et al. In vivo visualization of adventitial vasa vasorum of the human coronary artery on optical frequency domain imaging: Validation study. Circ J 2014; 78: 2516 – 2518. 14. Nishimiya K, Matsumoto Y, Uzuka H, Oyama K, Tanaka A, Taruya A, et al. Accuracy of optical frequency domain imaging for evaluation of coronary adventitial vasa vasorum formation after stent implantation in pigs and humans: A validation study. Circ J 2015; 79: 1323 – 1331. 15. Tian J, Ren X, Uemura S, Dauerman H, Prasad A, Toma C, et al. Spatial heterogeneity of neoatherosclerosis and its relationship with neovascularization and adjacent plaque characteristics: Optical coherence tomography study. Am Heart J 2014; 167: 884 – 892.e2, doi:10.1016/j.ahj.2014.03.013.
Circulation Journal Vol.79, August 2015
