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SECTION 1 Pathophysiology and investigation ofcoronary artery disease18
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9. Nishimiya K, Matsumoto Y, Takahashi J, Uzuka H, Wang H,
Tsuburaya R, etal. Enhanced adventitial vasa vasorum formation
in patients with vasospastic angina:assessment with OFDI. J Am
Coll Cardiol. 2016;67(5):598– 600.
10. Ohyama K, Matsumoto Y, Nishimiya K, Hao K, Tsuburaya R, Ota
H, etal. Increased coronary perivascular adipose tissue volume in
patients with vasospastic angina. Circ J. 2016;80(7):1653– 6.
11. Ozaki Y, Keane D, Serruys PW. Progression and regression of
coronary stenosis in the long- term follow- up of vasospastic
angina. Circulation. 1995;92(9):2446– 56.
12. Lin CS, Penha PD, Zak FG, Lin JC. Morphodynamic
interpretation of acute coronary thrombosis, with special
and evidence of ischaemia with non- obstructive coronary artery disease (INOCA), is the consequence of altered coronary microvascular
response to various stimuli despite non- obstructed epicardial vessels., e prevalence of INOCA in patients undergoing clinically
indicated angiography is as high as 20– 50%, is more oen encountered in women, and has adverse prognostic implications., Amajority of INOCA patients have coronary microvascular dysfunction
(CMD).– Studies implicate CMD and associations with heart
failure with preserved ejection fraction., Furthermore, CMD was
shown to predict adverse cardiovascular outcomes in women with
INOCA.
reference to volcano- like eruption of atheromatous plaque caused
by coronary artery spasm. Angiology. 1988;39(6):535– 47.
Coronary microvascularsystem
e coronary microvasculature determines blood ow distribution in the heart, maintaining balance of supply and demand. e
proximal part of the vascular system is responsive to ow- mediated
3.4 The coronary microcirculation
dilatation while the distal arterioles are responsive to changes in
intramyocardial concentration of metabolites. Ahallmark of the
coronary microvascular system is its heterogeneity (topological,
and coronary microvascular
dysfunction
morphological, and temporal) as a consequence of adaptation to
changing conditions and functional demands, although evaluation with cardiac positron emission tomography demonstrates
Romana Herscovici and C. Noel Bairey Merz
homogeneity of myocardial blood ow reduction in CMD. us,
CMD does not commonly translate to wall motion or segmental
e role of revascularization in the treatment of obstructive coronary artery disease is well established, and its impact on improving
survival has been proven. Nevertheless, patients with signs and
perfusion abnormalities on imaging.,
Coronary microvasculardysfunction
symptoms considered of cardiac origin but with no obstructive coronary artery disease on coronary angiography are increasingly seen.
Initially described as a ‘paradox’ or cardiac syndrome X and subsequently dened as microvascular angina, angina- like chest pain
Crea and colleagues proposed an updated clinical classication of
CMD (Table 3.4.1). e nal result of maladaptation may be ex-
plained by concomitant disturbances in several pathways. Classical
Table3.4.1 Coronary microvascular dysfunction classification
Type 1:in the absence of myocardial diseases and
obstructive CAD
Type 2:in myocardial diseases Hypertrophic cardiomyopathy
Type 3:in obstructive CAD Stable angina
Type 4:iatrogenic PCI
CAD, coronary artery diseases; PCI, percutaneous coronary intervention; SMC, smooth muscle cell.
Reproduced from Crea, F., P.G. Camici and C.N. Bairey Merz (2014). Coronary microvascular dysfunction:an update. Eur Heart J 35(17):1101– 1111 with permission from Oxford
University Press.
Clinical setting Main pathogenic mechanisms
Risk factors
Microvascular angina
Dilated cardiomyopathy
Anderson– Fabry’s disease
Amyloidosis
Myocarditis
Aortic stenosis
Acute coronary syndrome
Luminal obstruction
Coronary artery grafting
Endothelial dysfunction
SMC dysfunction
Vascular remodelling
Vascular remodelling
SMC dysfunction
Extramural compression
Luminal obstruction
Endothelial dysfunction
SMC dysfunction
Luminal obstruction
Autonomic dysfunction
3.4 The coronary microcirculation and coronary microvascular dysfunction 19
Endothelial and VSM dysfunction
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Predisposing
factors
Common
pathophysiology
Ischaemia
Clinical
manifestations
Traditional and novel risk factors
CMD
Angina
Microvascular remodelling
Spasm
Autonomic dysfunction
Abnormal myocardial
perfusion reserve
MACE
Fig.3.4.1 Potential predisposing factors, common pathophysiology, and clinical manifestations of coronary microvascular dysfunction (CMD). MACE,
major adverse cardiac event; VSM, vascular smooth muscle.
aetiologies include coronary endothelial, smooth muscle cell dysfunction, altered microvascular remodelling, spasm, and autonomic
dysfunction (Fig. 3.4.1). More recent and provocative hypotheses
address abnormalities in endothelial cell progenitors, degradation of
surface layer/ glycocalyx, compromised conduction, and convection.
constriction is signicantly modulated by endothelium- dependent
relaxation. us, alpha- adrenergic activation is an important determinant of microvascular resistance when impaired endothelial
function is present. Autonomic dysfunction was associated with
decreased coronary ow reserve in patients previously dened as
having cardiac syndrome X and damage to adrenergic receptors
Coronary endothelialdysfunction
In response to local haemodynamic, metabolic, and neurohormonal
was proposed as a mechanism of CMD in diabetic patients.
Coronary microvascularremodelling
signals, the normal endothelial cell produces mediators such as nitric
oxide and prostacyclin, promoting vasorelaxation, cardiomyocytesynchronized contraction, angiogenesis, and anti- inammatory responses. Under oxidative stress, endothelial cells release substances with
opposite eects (e.g. endothelin) resulting in vasoconstriction, microvascular rarefaction, and activation of inammatory processes.,
Chronic changes in vascular tone, circumferential wall tension, shear
stress, and metabolic demands eventually lead to structural remodelling. Studies of myocardial biopsies from patients with microvascular
angina and heart failure with preserved ejection fraction have found
evidence of sclerosis of small arteries and arterioles, perivascular brosis, swollen endothelial nuclei, and irregular lumina. Rarefaction
Smooth muscle celldysfunction
Reduced coronary blood ow in response to endothelialindependent vasodilators suggests primary impairment of smooth
muscle cells. Evidence now supports the model of an active and synergistic interaction between endothelial cells and smooth muscle
cells for vascular tone control.
may be an extreme stage of inward hypertrophic remodelling.
Relevance toclinicalcare
Diagnostic testing for CMD includes invasive coronary reactivity
testing, positron emission tomography, or cardiac magnetic resonance imaging., erapeutic lifestyle change, low- dose aspirin,
and lipid- lowering therapy are recommended due to the high preva-
Autonomicdysfunction
lence of coronary atherosclerosis and elevated risk of adverse cardiac
events, although evidence- based treatment guidelines currently do
not exist. Beta- blockers, angiotensin- converting enzyme inhibiAdrenergic receptors are widely spread in coronary microvasculature
with alpha- 1 adrenergic activation predominating in small arteries., Furthermore, coronary microvascular adrenergic- driven
tors, - arginine, nitrates, calcium channel blockers, ranolazine,
ivabradine, xanthine derivatives, alpha blockers, enhanced ex-
ternal counterpulsation, cognitive behavioural therapy, tricyclic
SECTION 1 Pathophysiology and investigation ofcoronary artery disease20
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medication, and neurostimulation can improve symptoms, stress
test parameters, and endothelial function. Large outcome trials
are needed in CMD subjects, as currently insucient data exist to
incorporate specic recommendations; however, aspects from existing angina and acute coronary syndrome guidelines are relevant
and can be deployed in this population.
Acknowledgements
is work was supported by contracts from the National Heart,
Lung and Blood Institutes nos. N01- HV- 68161, N01- HV- 68162,
N01- HV- 68163, N01- HV- 68164, grants U0164829, U01 HL649141,
U01 HL649241, K23HL105787, T32HL69751, R01 HL090957,
1R03AG032631 from the National Institute on Aging, GCRC grant
MO1- RR00425 from the National Center for Research Resources,
the National Center for Advancing Translational Sciences Grant
UL1TR000124 and UL1TR000064, and grants from the Gustavus
and Louis Pfeier Research Foundation, Danville, NJ, e Women’s
Guild of Cedars- Sinai Medical Center, Los Angeles, CA, e Ladies
Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, and
QMED, Inc., Laurence Harbor, NJ, the Edythe L. Broad and the
Constance Austin Women’s Heart Research Fellowships, CedarsSinai Medical Center, Los Angeles, California, the Barbra Streisand
Women’s Cardiovascular Research and Education Program, CedarsSinai Medical Center, Los Angeles, CA, e Society for Women’s
Health Research (SWHR), Washington, DC, e Linda Joy Pollin
Women’s Heart Health Program, and the Erika Glazer Women’s
Heart Health Project, Cedars- Sinai Medical Center, Los Angeles, CA.
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Duncker DJ, etal. Coronary vascular regulation, remodelling,
and collateralization:mechanisms and clinical implications on
behalf of the working group on coronary pathophysiology and
microcirculation. Eur Heart J. 2015;36(45):3134– 46.
16. Crea F, Camici PG, Bairey Merz CN. Coronary microvascular
dysfunction:an update. Eur Heart J. 2014;35(17):1101– 11.
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3.5 Plaque rupture anderosion 21
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24. Mehta PK, Bairey Merz CN. Treatment of angina in subjects with
evidence of myocardial ischemia and no obstructive coronary
artery disease. In:Bonow RO, ed. Braunwald’s heart disease. 9th
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brous cap characteristically occurs at the weakest point, typically at
the shoulder region. However, in plaque rupture that occurs during
exertion, we have observed rupture to occur more frequently at the
mid portion of the brous cap. erefore, dierent mechanisms
might contribute to the nal event of plaque rupture, that is, during
exercise versus at rest. Sukhova etal. have shown that select proteases secreted by macrophages weaken the brous cap. High shear
stress may also be involved; however, the absolute value of shear
3.5 Plaque rupture anderosion
stress is not sucient to directly provoke mechanical destruction of
the brous cap, and localized high shear stress might be a trigger of
brous cap rupture., We have shown apoptosis of macrophages
Hiroyoshi Mori, Sho Torii, and Renu Virmani
and smooth muscle cells are the main source of microcalcication
seen in atherosclerotic plaques. It had been suggested that triggers
Introduction
of rupture were due to interfacial debonding caused by the large
mismatch in material properties between the microcalcic deposits
and the surrounding collagenous tissue. However, Kelly- Arnold
Despite improvement in the treatment, prevention, and risk factor
management of atherosclerosis, the most frequent cause of death
globally remains coronary artery disease. erefore, it is essential
to understand the underlying mechanisms involved in the manifestation of acute coronary syndromes, sudden cardiac death, or stable
ischaemic heart disease. Coronary atherothrombosis is the main underlying cause of acute coronary syndromes. We will discuss the two
most frequent causes of atherothrombosis, that is, plaque rupture
and plaque erosion, in patients presenting with acute myocardial infarction or sudden coronary death.
etal., now suggest that aggregates of microvesicles of greater than
5 m located in the brous cap are more likely responsible for the
induction of stress concentration factors that lead to rupture. It is
also true that over 80% of plaque ruptures show larger calcied frag-
ments and plates in deep intimal locations near the intimal medial
border; however, how these may trigger plaque rupture remains
poorly understood.
e luminal thrombus seen at a rupture site is nearly always a
platelet- rich thrombus (white thrombus), which may or may not
be obstructive. e propagated thrombus both proximal and distal
to the rupture sites is a red thrombus composed of red cells separ-
Incidence andaetiology
ated by layers of brin (lines of Zahn). Proximally, the occlusive red
thrombus will usually extend to the nearest side branch and if the
thrombus is not removed will result in a large myocardial infarc-
In 1994, van der Wal etal. reported the incidence of plaque rupture
as 60% and that of erosion as 40% in a series of 20 individuals with
tion and the vessel will more likely progress to show chronic total
occlusion.
sudden coronary death. Subsequently, in 1996, our group reported
a 56% prevalence of plaque rupture and 44% for plaque erosion in a
series of 50 individuals; however, the age in the two series was sig-
Plaqueerosion
nicantly dierent (62.8years (range 32– 86years) vs 49±10years, respectively). In 2013, a review of a series of autopsy studies in patients
dying of hospital- based acute myocardial infarction and/ or sudden
coronary death reported that the most frequent aetiology of thrombosis was plaque rupture (65%), followed by erosion (30%), and calcied nodule (5%).
On multivariate analysis of risk factors, the lipid proles of high
total cholesterol and ratio (total cholesterol/ high- density lipoprotein cholesterol) were predictive of plaque rupture but not erosion.,
In contrast, smoking was signicantly associated with both. In our
sudden coronary death registry, erosion was more likely to occur in
premenopausal women and occurred in the presence of less plaque
burden and stenosis, and less calcication compared to that with
rupture.
Erosion lesions are commonly seen in young individuals, both men
and women, but are especially common in premenopausal women.
e luminal thrombus is in contact with a denudated endothelium
that overlies the underlying intima that is rich in smooth muscle cells
and proteoglycan matrix but has no contact with the underlying necrotic core if present. e underlying plaques of erosion lesions are
either pathological intimal thickening (16%) or have an early or late
broatheroma, 50% and 34%, respectively (Fig. 3.5.1b,c) e medial
wall in erosions is normally intact and the plaque is signicantly less
inamed than in ruptures. e tissue– thrombus boundary in erosion as reported previously is a proteoglycan- rich matrix composed
mainly of hyaluronan and type III collagen, while the brous cap in
ruptured and stable plaques is rich in biglycan, and decorin., With
time, stable plaques are mostly composed of type Icollagen. Overall,
Plaquerupture
erosion lesions show less calcication with more than half of erosions
(56%) showing no calcication, while 40% show microcalcication
and fragmented and sheet of calcication is rarely observed (2%).
Plaque rupture is characterized by having a large necrotic core with
an overlying disrupted thin brous cap (23±19 m) (Fig. 3.5.1a).
e thin cap is generally inltrated by macrophages and T lymphocytes. e extracellular matrix of the brous cap is mainly composed
of type Icollagen with very few smooth muscle cells. Rupture of the
Unlike plaque rupture, erosions tend to show negative remodel-
ling., At this time, no distinct morphological features indicative of
erosion- prone lesions have been identied. e aetiology of plaque
erosion remains unknown although we suspect that vasospasm may
play a role.
SECTION 1 Pathophysiology and investigation ofcoronary artery disease22
Rupture
Erosion
(a)
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Underlying PIT Underlying FA
(c)(b)
Th
Th
NC
Smooth muscle cells
Macrophage foam cells
Extracellular lipid
Cholesterol clefts
Necrotic core
Calcified plaque
Collagen
Hemorrhage
Thrombus
Healed thrombus
Angiogenesis
Fibrin
Th
NC
2.0 mm
200 μm
Th
1.0 mm
100 μm
1.0 mm
Th
100 μm
Fig.3.5.1 Human coronary lesion morphologies categorized as ‘lesions with acute thrombi’. Histological and schematic images are shown for
(a)plaque rupture, (b)plaque erosion with underlying pathological intimal thickening (PIT), and (c)plaque erosion with underlying fibroatheroma (FA).
Arrowheads indicate fibrous cap. NC, necrotic core; Th, thrombus.
Reproduced from Yahagi K, Kolodgie FD, Otsuka F etal. Pathophysiology of native coronary, vein graft, and in- stent atherosclerosis. Nat Rev Cardiol 2016;13:79– 98 with permission
from Springer.
e thrombi of eroded plaques oen exhibit a later stage of organization than those of ruptured plaques in autopsy studies.
Most of the thrombi in erosion (88%) showed late- stage thrombi
compared with 54% of the thrombi in rupture (P <0.0001).
Downstream embolizations caused by fragments of coronary
thrombi are another frequent complication of plaque erosion. e
majority of patients with erosion (71%) showed intramyocardial
microemboli while only 42% of patients with rupture showed
downstream emboli.
Conclusion
Plaque rupture and erosion are the two major aetiologies of
acute coronary thrombosis. Plaques that rupture versus those
that manifest erosion present with dierent underlying features.
Avulnerable plaque, also known as thin cap broatheroma, is characteristic of rupture while erosive plaques are broatheromatous
(broatheroma) in over half of cases while the remainder have
pathological intimal thickening. ere are dierences in the
incidence, aetiology, morphological features, and risk factors that
lead to rupture and erosion.
REFERENCES
1. World Health Organization. e top 10 causes of death:fact sheet
N°310. [Internet]. Geneva:World Health Organization; 2013.
Available from:https:// www.who.int/ news- room/ fact- sheets/
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2. van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of
intimal rupture or erosion of thrombosed coronary atherosclerotic
plaques is characterized by an inammatory process irrespective of
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100
Percent survival
93.4%
88.0%
81
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3.6 Biology ofbypass vessels and their relation topatency anddisease 23
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by interstitial collagenases- 1 and - 3 in vulnerable human
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J, etal. Localized elevation of shear stress is related to coronary
plaque rupture. A3- dimensional intravascular ultrasound study
with in- vivo color mapping of shear stress distribution. J Am Coll
Cardiol. 2008;51(6):645– 50.
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cap rupture in human coronary arteries. Proc Natl Acad Sci USA.
2013;110(26):10741– 6.
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in culprit lesions:insights into plaque erosion. Arterioscler
romb Vasc Biol. 2002;22(3):1642– 8.
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investigation and reports morphological predictors of arterial
remodeling in coronary atherosclerosis. Circulation. 2002;105:297– 303.
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DR, Liang YH, etal. Relationship of thrombus healing to
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3.6 Biology ofbypass vessels and
their relation topatency anddisease
Thomas F. Lüscher
Background
Current standard surgical technique in patients undergoing coronary bypass graing involves the use of an internal mammary
90
80
70
60
2
46
Years
Internal mammary artery n = 332
Saphenous vein graft n = 440
p = 0.05
0
Fig.3.6.1 Patency rate of internal mammary artery grafts compared to
venous grafts of time.
Loop FD, Lytle BW, Cosgrove DM, Stewart RW, Goormastic M, Williams GW, etal.
Influence of the internal- mammary- artery graft on 10- year survival and other cardiac
events. N Engl J Med. 1986;314(1):1– 6.
artery (also known as an internal thoracic artery) bypass gra, in
general to the le anterior descending coronary artery, and in many
centres also the use of the right internal mammary artery to the right
coronary artery. Several clinical studies have shown the superiority
of mammary artery bypass gras for survival of patients compared
to the use of venous bypass gras alone (Fig. 3.6.1). Indeed, the internal mammary artery has several biological features, discussed in
this chapter, that are remarkable and of great interest for biologists,
cardiologists, and surgeons alike.
Coronary bypassvessels
Over the years, numerous blood vessels have been used for coronary artery bypass graing, starting with the saphenous vein in
1967 by René Favaloro who pioneered this operation and later with
the use of the internal mammary artery, the radial artery, the right
gastroepiploic artery, and the epigastric artery. All these blood vessels dier remarkably in their function and structure as well as patency when implanted into the coronary circulation as gras.
Of note, the saphenous vein, when used as a coronary bypass
gra, is prone to bypass gra disease and eventual occlusion
(Fig. 3.6.2); indeed, intimal hyperplasia and plaque formation
develops continuously over time in venous bypass vessels aer
implantation and aer 10 years most venous bypass gras are
occluded. In contrast, the internal mammary artery shows the
highest patency rate (Fig. 3.6.1), while the radial artery and the
gastroepiploic artery give less satisfactory results, due to their
propensity towards spasm, especially when patients require catecholamines aer operation; they are today much less commonly
used than the former.
ese remarkable dierences in the function of bypass vessels are
of great interest from a biological point of view, as it must reect the
SECTION 1 Pathophysiology and investigation ofcoronary artery disease24
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Fig.3.6.2 Patency of an internal mammary artery bypass graft (a)and venous bypass graft disease (b)of a saphenous vein implanted into the left
anterior descending coronary artery.
dierent biological properties of these blood vessels. Of note, even
in patients with three- vessel disease, the internal mammary artery
is usually angiographically completely free of plaques (Fig. 3.6.2a)
despite exposure to the same blood pressure, lipid values, and blood
glucose levels as coronary arteries. Hence, the internal mammary
artery and to some degree also the radial and gastroepiploic arteries must be protected from atherosclerosis thanks to specic biological properties of their endothelial and/ or smooth muscle cells or
broblasts.
is chapter updates previously published reviews by the author,
and outlines the biological properties of endothelial cells as well as
vascular smooth muscle cells of arterial gras compared to venous
bypass vessels.
as tissue factor and plasminogen activator inhibitor as discussed
later in this section.
First of all, the endothelium activates, thanks to the expression
of angiotensin- converting enzyme on its surface, angiotensin Iinto
angiotensin II and breaks down bradykinin, a process that is more
pronounced in the saphenous vein than it is in the internal mammary artery. Inhibition of angiotensin- converting enzyme, therefore, increases endothelium- dependent relaxation to bradykinin in
the saphenous vein, but not in the mammary artery.
e endothelial - arginine pathway is an important local regulator of platelet vessel wall interactions as well as of vascular tone
(Fig. 3.6.4). e end product of the pathway, NO, is formed from
- arginine, and activates soluble guanylyl cyclase (leading to increased cyclic guanosine monophosphate (cGMP)) by binding to its
Endothelialcells
ferrous ring leading to a conformational change that activates the
enzyme and eventually reduces intracellular calcium concentration
and in turn induces vasodilation and platelet inhibition, respectively.
Endothelial cells cover the entire arterial, venous, and lymphatic
circulation and play an important role as sensors and regulators
of blood vessel wall interactions and regulate both vasomotion as
well as vascular structure. Of note, under physiological conditions
the endothelium is an activator, as well as an inactivator, of circulating and local hormones such as angiotensin I, and bradykinin
and serotonin, respectively. Furthermore, it may, through the release of acetylcholine, histamine, and many other autocoids of
vasoactive substances, induce vasodilation through nitric oxide
(NO) (Fig. 3.6.3) or vasoconstriction through endothelin (ET)
via both ETA and ETB receptors; modulate the interaction of white
blood cells, in particular monocytes with the vessel wall; and also
regulate growth of vascular smooth muscle cells. Finally, the endothelium is a source of antithrombotic, that is, prostacyclin and
tissue plasminogen activator, and prothrombotic molecules such
Of note, the release of NO in response to receptor- operated agonists
such as bradykinin, acetylcholine, adenosine diphosphate (ADP), or
thrombin is much less pronounced or absent in the saphenous vein
than it is in the internal mammary artery. e gastroepiploic artery, however, has an endothelial function that is similar to that of
the internal mammary artery.
Importantly, all bypass vessels respond with vasodilation when
exposed to nitrovasodilators indicating that the vascular smooth
muscle cells are capable of forming cGMP. In the gastroepiploic artery,
the accumulation of cGMP aer stimulation with nitrovasodilators
is even more pronounced than with other bypass vessels, as are contractions to vasoconstrictor substances such as norepinephrine.
Regulation of platelet/ vessel wall interactions is of particular
importance in graft functioning and may prevent graft occlusion. In this context, it is of interest that the platelet- derived
3.6 Biology ofbypass vessels and their relation topatency anddisease 25
Response, percent of the contraction
Internal mammary artery Saphenous vein
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20
0
L-NMMA +
Indo n = 5
40
20
0
40
60
to norepinephrine
L-NMMA
n = 4
–20
–40
–60
80
–80
100
9
8
76 5
100
Indo n = 6
control
9
76 54
8
n = 4
Acethylcholine (–logM)Acethylcholine (–logM)
Control n = 5
Indomethacin n = 5
L-NMMA n = 4 Without endothelium n = 4
Fig.3.6.3 Activity of the l- arginine– nitric oxide pathway in the human internal mammary artery (left) and saphenous vein (right).
Reproduced from Yang Z, Von Segesser L, Bauer E, Stulz P, Turina M, Lüscher T.Different activation of the endothelial L- arginine and cyclooxygenase pathway in the human internal
mammary artery and saphenous vein. Circulation Research. 1991;68(1):52– 60 with permission from Wolters Kluwer.
mediator ADP binds specific receptors on endothelial cells and
induces NO release, thereby inhibiting platelet function via accumulation of cGMP and induction of vasodilation in the mammary artery, a response that is conversely weak or absent in
the saphenous vein (Fig. 3.6.5). Thus, the internal mammary
artery exhibits endothelium- dependent relaxation and inhibition of platelet function at sites where platelets are activated
and thereby is protected from thrombus formation. Of note,
thrombin exerts dual effects on the endothelium and platelets
as it induces endothelium- dependent relaxation via NO in the
Bk
SP
B
1
cGMP
Vascular
smooth
muscle cells
Fig.3.6.4 The l- arginine– nitric oxide pathway in the mammary artery and saphenous vein regulating vascular tone and structure and platelet– vessel
wall interaction.
Reproduced from Lüscher TF. Vascular biology of coronary bypass grafts. Coronary Artery Disease. 1992;3(2):157– 65 with permission from Wolters Kluwer.
Internal mammary artery
Thr
+
PThr
cGMP
–
PThr
ATP
ADP
Thr
P
T
P
2
NO
Relaxation
Platelets
TXA
Ach
M
TX
cGMP
2
TGF
β
Endothelin
ET
Contraction
+
PThr 5-HT
Thr
T
ET
B
A
Endothelial
cells
S
2
Vascular
smooth
muscle cells
PThr
PThr
Bk
B
1
cGMP
Relaxation
Saphenous vein
Thr
+
cGMP
–
ATP
ADP
NO
Platelets
Ach
M
TXA
TX
cGMP
2
TGF
β
Endothelin
ET
Contraction
+
PThr 5-HT
Thr
T
ET
B
A
Endothelial
cells
S
2
SECTION 1 Pathophysiology and investigation ofcoronary artery disease26
Relaxation, percent of the contraction
75
Saphenous vein
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Internal mammary artery
0
20
40
to norepinephrine
60
80
1
With endothelium:
2.5 10 25 50 75 1 2.5 10 25 50
Platelets (103/μl)
Control (n = 5)
Apyrase (n = 4)
L-NMMA (n = 4)
Without endothelium (n = 5)
140
120
100
80
60
to norepinephrine
40
Contraction, percent of the response
20
0
Endothelium:
With
Without (n = 5)
Fig.3.6.5 Effects of aggregating platelets in the mammary artery and saphenous vein. Apyrase breaks down ATP and ADP released from platelets; l-
NMMA, l- N monomethyl arginine, a competitive inhibitor of l- arginine blocking NO production.
Reproduced from Yang ZH, Stulz P, von Segesser L , Bauer E, Turina M, Luscher TF. Different interactions of platelets with arterial and venous coronary bypass vessels. Lancet.
1991;337(8747):939– 43 with permission from Elsevier.
mammary artery and causes direct aggregation of platelets.
Indeed, in the presence of normally functioning endothelium,
flow through the graft is maintained and activated platelets
are flushed away and disaggregated to prevent development
of platelet clot. Interestingly, the gastroepiploic artery also exhibits marked contractions to aggregating platelets similar to
the saphenous vein. This, together with its marked contractile
responses to catecholamines, may explain the less favourable results seen when it is used as a bypass graft.
Endothelial cells express several receptors that are linked to
the - arginine– NO pathway such as bradykinin, histamine,
ADP, serotonin, thrombin, and substance P. In the mammary
and gastroepiploic arteries, besides acetylcholine, and particularly bradykinin, histamine and substance P as well as ADP released from aggregating platelets exhibit endothelium- dependent
relaxations,,, which are less pronounced or absent in the
saphenous vein.
Importantly, shear stress exerted by the circulating blood also induces
the release of NO which is an important mechanism of ow- mediated
vasodilation during exercise or under other conditions of increased
demand. is response is crucial for the function of mammary artery gras when they are implanted into the coronary circulation and
exposed to marked increases in ow. Indeed, when arterial gras are
implanted into coronary segments with haemodynamically insignicant stenoses, they tend to shrink or even occlude (angiographically
described as the ‘string sign’). us, in summary, NO is an important
regulator of the physiological function of bypass vessels during rest and
under conditions of increased demand, such as during exercise.
Prostacyclin is another endothelial mediator, which activates
cyclic AMP in platelets and vascular smooth muscle. In platelets, prostacyclin is a potent inhibitor of aggregation, particularly
in synergy with NO, and therefore plays a protective role in the
circulation. Indeed, NO and prostacyclin act in concert and potentiate each other’s action particularly in platelets and, therefore,
contribute to the antithrombotic properties of the endothelium.
Finally, endothelial cells also produce tissue plasminogen activator as do vascular smooth muscle cells. Of note, vascular smooth
muscle cells of the internal mammary artery release much more
tissue plasminogen activator and less tissue plasminogen inhibitor or plasminogen activator inhibitor 1 compared to the saphenous vein. is again demonstrates that mammary arteries
are protected from clot formation, while this oen occurs in the
saphenous veins in particular in the absence of eective platelet
inhibition.
Structural vascularchanges
e internal mammary artery is further remarkable as— even in patients with severe three- vessel disease— it remains patent and angiographically smooth. Histological analysis shows that the internal
mammary artery exhibits little structural changes and in particular
rarely develops plaques (Fig. 3.6.6). is is obviously in sharp contrast to the saphenous vein when implanted into the coronary circulation where it exhibits marked intimal hyperplasia and develops
atherosclerotic changes.
3.6 Biology ofbypass vessels and their relation topatency anddisease 27
Age
Intimal thickness (r)
7
Internal mammary arterySaphenous vein
https://t.me/medicina_free
6
5
4
3
2
Coronary artery
Endothelium
Internal elastic lamina
Media
1
0102030
Internal mammary artery
40 50 60
Adventitia
Orcein-Hx
Fig.3.6.6 Structural vascular changes in the human coronary and mammary artery with age.
Sims FH. The pathology of the internal thoracic artery and its contribution to the study of atherosclerosis. In:Green GE, Singh RN, Sosa JA, eds. Surgical revascularization of the
heart:the internal thoracic arteries. NewYork, NY:Igaku- Shoin; 1991;18– 62.
e remarkable clinical dierences of mammary artery and venous
gras can be explained by their dierent biological properties. Besides
endothelial cells, vascular smooth muscle cells of both blood vessels
markedly dier. Indeed, explants of the media of the saphenous vein
exhibit an extensive outgrowth of smooth muscle cells, while this is
hardly the case with explants of the mammary artery (Fig. 3.6.7).
Furthermore, when stimulated with platelet- derived growth factor
(PDGF), saphenous vein vascular smooth muscle cells rapidly and
markedly grow, while this is again hardly the case with mammary artery cells. Finally, and this might be of utmost importance for venous
bypass gra disease, saphenous vein smooth muscle cells grow rapidly
when exposed to pulsatile stretch, while mammary cells are protected
from this physical stimulus. us, when implanted into the coronary
circulation, the saphenous vein, which physiologically is exposed to
laminar ow and low shear stress in the venous circulation, will develop a marked intimal hyperplasia leading in part to narrowing of the
lumen and eventually gra attrition (Fig. 3.6.8).
Ex vivo genetransfer
Big hopes rested on the prospects of gene therapy. Unfortunately, this
approach turned out to be more complex than initially anticipated.
Nevertheless, ex vivo gene transfer is possible and has been investigated
in pilot studies. Indeed, migration and proliferation of smooth muscle
cells importantly contributes to intimal thickening and vascular remodelling in venous bypass gra disease. Almost all peptide growth
factors such as platelet- derived growth factor released from aggregating platelets are potent activators of smooth muscle cells migration.
In a rst pilot study, in human saphenous vein smooth muscle cells
NO provided by the overexpression of the gene encoding endothelial
NO synthase (NOS3) with a recombinant adenovirus vector or added
directly through an NO donor inhibits the migration in response to
PDGF via inhibition of the Rho Apathway. Indeed, adenoviral endothelial NO synthase transfection inhibits proliferation and migration
of human saphenous vein vascular smooth muscle cells in response
to 20% serum to a similar degree as an exogenous NO donor such as
diethylenetriamine NONOate.
As a next step, we transfected intact saphenous vein tissue ex
vivo aer surgical explantation. Ecient transfection was demonstrated by staining of saphenous vein tissue for placental alkaline
phosphatase. Consistent with this observation, endothelial NO synthase protein expression and NO release were indeed enhanced in
transfected venous tissue. Furthermore, endothelial NO synthase
overexpression inhibited vascular smooth muscle cell outgrowth
from saphenous vein explants. Similarly, platelet adhesion to human
saphenous vein tissue was reduced by endothelial NO synthase
Fig.3.6.7 Outgrowth of smooth muscle cells from explants obtained
from a saphenous vein (left) or an internal mammary artery (right). Note
the extensive outgrowth in the saphenous vein and the modest response
in the mammary explant.
Reproduced from Yang Z, Oemar BS, Carrel T, Kipfer B, Julmy F, Lüscher TF. Different
proliferative properties of smooth muscle cells of human arterial and venous bypass
vessels role of PDGF receptors, mitogen- activated protein kinase, and cyclin- dependent
kinase inhibitors. Circulation. 1998;97(2):181– 7 with permission from Wolters Kluwer.
overexpression under these conditions. us, endothelial NO
synthase gene transfer is technically feasible ex vivo and inhibits
biological features of bypass gra disease in the intact human saphenous vein tissue that are related to gra failure.
is approach provides the basis for innovative preoperative
treatments for the prevention of venous bypass gra disease that appear worthwhile to be tested in the future. Indeed, the PREVENT
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