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SECTION 1 Pathophysiology and investigation ofcoronary artery disease8
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66. Nashef SAM, Roques F, Michel P, Gauducheau E, Lemeshow S,
Salamon R. European system for cardiac operative risk evaluation
(EuroSCORE). Eur J Cardiothorac Surg. 1999;16(1):9– 13.
67. Falk V, Diegeler A, Walther T, Autschbach R, Mohr F. Developments
in robotic cardiac surgery. Curr Opp Cardiol. 2000;15(6):378– 87.
68. Buxton BF, Raman JS, Ruengsakulrach P, Gordon I, Rosalion
A, Bellomo R, etal. Radial artery patency and clinical
outcomes:ve- year interim results of a randomized trial. J orac
Cardiovasc Surg. 2003;125(6):1363– 71.
69. Taggart DP, Benedetto U, Gerry S, Altman DG, Gray AM, Lees
B, etal. Bilateral versus single internal- thoracic- artery gras at
10years. N Engl J Med. 2019;380(5):437– 46.
70. Desai ND, Cohen EA, Naylor CD, Fremes SE, Radial Artery
Patency Study Investigators. Arandomized comparison of radialartery and saphenous- vein coronary bypass gras. N Engl J Med.
2004;351(22):2302– 9.
71. Collins P, Webb CM, Chong CF, Moat NE, Radial Artery Versus
Saphenous Vein Patency (RSVP) Trial Investigators. Radial
artery versus saphenous vein patency randomized trial:ve- year
angiographic follow- up. Circulation. 2008;117(22):2859– 64.
72. Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes
DR, Mack MJ, etal. Percutaneous coronary intervention versus
coronary- artery bypass graing for severe coronary artery
disease. N Engl J Med. 2009;360(10):961– 72.
73. Cleland JG, Calvert M, Freemantle N, Arrow Y, Ball SG, Bonser
RS, etal. e Heart Failure Revascularisation Trial (HEART). Eur
J Heart Fail. 2011;13(2):227– 33.
74. Velazquez EJ, Lee KL, Jones RH, Al- Khalidi HR, Hill JA, Panza
JA, etal. Coronary- artery bypass surgery in patients with
ischemic cardiomyopathy. N Engl J Med. 2016;374(16):1511– 20.
75. Farkouh ME, Domanski M, Sleeper LA, Siami FS, Dangas G,
Mack M, etal. Strategies for multivessel revascularization in
patients with diabetes. N Engl J Med. 2012;367(25):2375– 84.
76. Lamy A, Devereaux PJ, Prabhakaran D, Taggart DP, Hu S, Straka
Z, etal. Five- year outcomes aer o- pump or on- pump coronaryartery bypass graing. N Engl J Med. 2016;375(24):2359– 68.
77. Stone GW, Sabik JF, Serruys PW, Simonton CA, Généreux
P, Puskas J, etal. Everolimus- eluting stents or bypass
surgery for le main coronary artery disease. N Engl J Med.
2016;375(23):2223– 35.
78. Gaudino M, Benedetto U, Fremes S, Biondi- Zoccai G,
Sedrakyan A, Puskas JD, etal. Radial- artery or saphenousvein gras in coronary- artery bypass surgery. N Engl J Med.
2018;378(22):2069– 77.
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2
Epidemiology ofischaemic heartdisease
Nick Townsend
Ischaemic heart disease (IHD) is the single leading cause of death
worldwide. e Global Burden of Disease study estimated that IHD
caused more than 8.9million deaths in 2015, accounting for 15.9%
of total deaths that year. Of these 8.9million IHD deaths, 4.9million occurred in men and 4.0million in women.
IHD accounts for similar percentages of all deaths for both sexes
(men=15.9%; women=16.2%). However, global age- standardized
mortality rates (ASMRs) are much lower in women (115.0/ 100,000)
than in men (172.8/ 100,000) as standardization allows us to control
for the greater longevity of women. is is important as IHD is more
common at older ages. Similarly, although the number of deaths due
to IHD rose from 7.6million in 2005 to 8.9million in 2015, this
was largely due to an increasing population and progressive ageing.
Global ASMRs over the same period of time decreased from 163/
100,000 to 142/ 100,000.
Of the 8.9 million global IHD deaths, 3.2million occurred in
those under the age of 70years, otherwise dened as premature
mortality., e World Health Organization has declared that these
current rates of premature deaths are unacceptable, as cost- eective
interventions to prevent IHD are available. As with total deaths,
premature IHD mortality is a greater burden among men than
women. Around 2.2million IHD deaths occur in men under the
age of 70years, equivalent to around 45% of all IHD deaths in males.
is compares to just under 1million premature deaths in women,
equivalent to less than 25% of all IHD deaths in females.
Years of life lost (YLL) is a metric that takes into account the age at
which deaths occur, by relating age at death to a standard life expectancy, thereby giving greater weight to deaths at younger ages. IHD is
the greatest cause of YLL globally, having moved up from the fourth
greatest cause in 1990, when it was ranked behind preterm birth,
diarrhoeal diseases, and lower respiratory infections., e Global
Burden of Disease study estimates that in 2015, 99million years of
life were lost on account of IHD in men globally, with 57million lost
in women. ese sex dierences were greater among those under
70years of age, among whom 70million years of life were lost in
men, compared to 29million in women.
A number of people surviving IHD are still aected by it; therefore, the health impact of IHD is not only due to the deaths it causes,
but also to the burden of disability in those who survive with it. IHD
was the leading cause of disability- adjusted life years (DALYs) in
2015. e DALY is a health gap measure that extends the concept
of potential YLL due to premature death to include equivalent years
of ‘healthy’ life lost by virtue of being in a state of poor health or
disability. ere was an 11% increase in global DALYs due to IHD,
from 147.8million in 2005 to 164.0million (men=103.2million,
women=60.8 million) in 2015, despite a 14.2% decrease in agestandardized DALYs over the same period of time.
ese increases in DALYs have occurred, in part, due to the rising
global prevalence of IHD. e number of people living with IHD increased from 87.5million people in 2005 to 110.6million in 2015. As
with deaths, this increase in prevalence is inuenced by the growing
population size and increasing longevity, demonstrated by a decrease of 3.4% in age- standardized prevalence rates over the same
period of time. Agreater prevalence of IHD was found among men
(64.4million) than women (46.1million) in 2015, with these sex differences greater for those under 70years, among whom 44.1million
men have suered IHD compared to 25.5million women.
Although IHD is recognized as the most common cause of death
globally, there is great variation between countries in the probability of dying from IHD, with this ranging from 0.8% for women
in Japan to more than 24% for men in Belarus., Although IHD
is the top cause of YYLs in developed countries, it is second to
lower respiratory infection in developing countries., Despite this,
only around 22% of global IHD deaths occur in high- income (developed) countries, with this disparity greater for premature IHD
deaths, 88% of which occur in developing countries. High- income
countries also have the lowest IHD ASMRs (87.9/ 100,000), with
ASMRs for men in high- income countries lower than those for
women in all developing country classications (Fig. 2.1). Within
developing countries, lower middle- income countries have the
highest ASMRs (207.4/ 100,000), higher rates than found in both
low- income (153.4/ 100,000) and upper middle- income (142.8/
100,000) countries.
e World Health Organization has identied eight key risk
factors that lead to IHD, including modiable (behavioural) risk
factors— alcohol use, tobacco use, diet, and physical inactivity— and
intermediate (medical/ physiological) risk factors— high blood pressure, high body mass index, high cholesterol, and high blood glucose., It is estimated that together these risk factors account for
over three- quarters of deaths from IHD.
SECTION 1 Pathophysiology and investigation ofcoronary artery disease10
Age-standardized IHD mortality rates
300
income
income
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2. Nowbar AN, Howard JP, Finegold JA, Asaria P, Francis DP.
2014 Global geographic analysis of mortality from ischaemic
250
200
150
100
per 100,000 population
50
0
Males
Low income
Females Females Females Females
Males
Lower
middle
Males
Upper
middle
Males
High
income
Fig.2.1 Age- standardized mortality rates for ischaemic heart disease by
World Bank income classification of country and sex, 2015. Note:rates
age standardized to the 2013 Global Burden of Disease standard
population.
Source data from Global Burden of Disease Results Tool (http:// ghdx.healthdata.org/
gbd- results- tool).
REFERENCES
1. GBD 2015 Mortality and Causes of Death Collaborators. Global,
regional, and national life expectancy, all- cause mortality, and
cause- specic mortality for 249 causes of death, 1980– 2015:a
systematic analysis for the Global Burden of Disease Study 2015.
Lancet;388(10053):1459– 544.
heart disease by country, age and income:Statistics from
World Health Organization and United Nations. Int J Cardiol.
2014;174(2):293– 8.
3. GBD 2013 Mortality and Causes of Death Collaborators. Global,
regional, and national age- sex specic all- cause and causespecic mortality for 240 causes of death, 1990– 2013:a systematic
analysis for the Global Burden of Disease Study 2013. Lancet.
2015;385(9963):117– 71.
4. World Health Organization. Global status report on noncommunicable diseases 2014. Geneva:World Health Organization; 2014.
5. Kassebaum NJ, Arora M, Barber RM, Bhutta ZA, Brown J, Carter
A, etal. Global, regional, and national disability- adjusted life- years
(DALYs) for 315 diseases and injuries and healthy life expectancy
(HALE), 1990– 2015:a systematic analysis for the Global Burden of
Disease Study 2015. Lancet. 2016;388(10053):1603– 58.
6. GBD 2015 Disease and Injury Incidence and Prevalence
Collaborators. Global, regional, and national incidence,
prevalence, and years lived with disability for 310 diseases and
injuries, 1990– 2015:a systematic analysis for the Global Burden of
Disease Study 2015. Lancet. 2016;388(10053):1545– 602.
7. World Health Organization. Chronic diseases and their common
risk factors [Internet]. Geneva:World Health Organization; 2005.
Available from:http:// www.who.int/ chp/ chronic_ disease_ report/
media/ Factsheet1.pdf
8. World Health Organization. Global health risks:mortality
and burden of disease attributable to selected major risks.
Geneva:World Health Organization; 2009.
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3
Pathophysiology ofcoronary
arterydisease
reserve. Maximum perfusion and coronary ow reserve are reduced
3.1 Regulation of coronary flow
Nico Bruining, Eric Boersma, and Dirk J. Duncker
e le ventricle (LV) generates the systemic arterial blood pressure
that is required to maintain coronary blood ow (CBF). e coronary circulation is unique among regional vascular beds in that its
perfusion is impeded during the systolic phase of the cardiac cycle
by the surrounding contracting cardiac muscle. Systolic contraction increases LV wall tension and compresses the intramyocardial
microvessels, thereby impeding coronary arterial inow. is compression is not uniformly distributed across the LV wall, resulting
in a redistribution of blood ow from the subendocardium to
subepicardium.
LV myocardial oxygen extraction averages 60– 80% of arterially
supplied oxygen at rest., Consequently, increases in myocardial
oxygen consumption (e.g. during exercise) are predominantly met
by proportional increases in CBF., e increase in CBF is principally the result of a reduction in coronary vascular resistance, due
to dilation of coronary small arteries and arterioles, the so- called resistance vessels. Currently no consensus exists regarding which specic mediators regulate the decrease in coronary vascular resistance
during increased LV metabolic activity, which is likely the result of
considerable redundancy in locally available control mechanisms.
CBF remains fairly constant over a wide range of coronary perfusion pressures,, owing to adjustments in the diameter of coronary
resistance vessels mediated by both myogenic and metabolic mechanisms. is autoregulation of blood ow is particularly important
to maintain CBF when coronary perfusion pressure is decreased by
an upstream coronary artery stenosis. e pressure at which the
coronary resistance vessels become maximally dilated is the lowest
pressure at which normal myocardial blood ow can be maintained,
and is referred to as the lower limit of autoregulation. Below this
coronary pressure, CBF decreases in a pressure- dependent manner,
leading to myocardial ischaemia. Under normal haemodynamic
conditions, resting LV myocardial blood ow averages 0.7– 1.0 mL/
min/ g of myocardium and can increase four- to vefold during maximal vasodilation.,, e ability to increase CBF above resting levels
in response to pharmacological vasodilation is termed coronary ow
when the diastolic time available for subendocardial perfusion is decreased (e.g. as with tachycardia) or the compressive determinants
of diastolic perfusion (i.e. LV diastolic pressures) are increased.,,
Coronary reserve is also reduced when resting ow is increased, for
example, in response to increases in oxygen consumption (heart
rate, systolic pressure, and LV contractility) (Fig. 3.1.1) or with reductions in arterial oxygen content (anaemia and hypoxia). Hence,
conditions can arise that favour the development of myocardial ischaemia in the presence of normal coronary arteries. Investigations
in conscious animals in a basal resting state have demonstrated that
autoregulation can maintain resting CBF in the presence of coronary perfusion pressures as low as 40mmHg., ese levels of
coronary pressures are similar to coronary pressures recorded in
humans without symptoms of ischaemia during balloon occlusions,
using pressure wires. e lower pressure range of autoregulation
increases during tachycardia due to an increase in ow requirements
in conjunction with a decrease in diastolic perfusion time.,
Subendocardial ow occurs primarily in diastole and resistance
vessels are maximally vasodilated below a mean coronary pressure
of 40mmHg. In contrast, subepicardial ow occurs throughout the
cardiac cycle and is maintained until coronary pressure falls below
25mmHg. is dierence is the result of a more pronounced eect
of systolic contraction on subendocardial vasodilator reserve, together with higher levels of subendocardial oxygen consumption,
requiring higher resting CBF levels. e transmural dierence in
the minimal autoregulatory pressure translates into increased vulnerability of the subendocardium to ischaemia in the presence of a
coronary stenosis.
As described previously, identifying the ow- limiting characteristics of a coronary lesion is of utmost importance and measuring
this in the interventional setting is mostly performed by measuring
the fractional ow reserve (FFR) aer adenosine infusion to obtain
maximal coronary hyperaemia. In the catheterization laboratory,
FFR measurements are instrumental to identify ow- limiting coronary stenoses capable of causing myocardial ischaemia. In order
to improve clinical outcomes, patients with lesions with low FFR
values may then be candidates for revascularization, either with
percutaneous coronary intervention (PCI) or coronary bypass surgery. Evidence exists that so- called optimal medical treatment, including drugs for angina relief and event prevention, in ischaemic
SECTION 1 Pathophysiology and investigation ofcoronary artery disease12
Coronary pressure
Coronary flow (mL/min/g)
Normal
Stress
Coronary pressure
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5.0
3.0
1.0
P
RA
mmHg
Maximum
vasodilation
40
P
f = 0
Flow reserve
normal
Maximum
vasoconstriction
Autoregulatory
range
5.0
3.0
1.0
Decreased maximum flow
LV hypertrophy
Microvascular disease
↑ HR
↑ Preload
Maximum
vasodilation
60
mmHg
Increased resting flow
↑ HR
↑ SBP
↑ Contractility
↑ Hb
Flow reserve
stress
Fig.3.1.1 Autoregulatory relation under basal conditions and following metabolic stress (e.g. tachycardia). The normal heart maintains CBF constant
(left panel) as regional coronary pressure is varied over a wide range when the global determinants of oxygen consumption are kept constant (red
lines). Below the lower autoregulatory pressure limit (approximately 44mmHg), subendocardial vessels are maximally vasodilated and myocardial
ischaemia develops. During vasodilation (blue lines), flow increases four to five times above resting values at a normal arterial pressure. Coronary flow
ceases at a pressure higher than right atrial pressure (PRA), called zero flow pressure (Pf=0), which is the effective back pressure to flow in the absence
of coronary collaterals. Following stress (right panel), tachycardia increases the compressive determinants of coronary resistance by decreasing the time
available for diastolic perfusion and thus, reduces maximum vasodilated flow. Increases in myocardial oxygen demand or reductions in arterial oxygen
content (e.g. from anaemia or hypoxaemia) increase resting flow. These changes reduce coronary flow reserve, the ratio between dilated and resting
coronary flow, and cause ischaemia to develop at higher coronary pressures. Hb, haemoglobin; HR, heart rate; LV, left ventricular; SBP, systolic blood
pressure.
Canty JM, Duncker DJ. Coronary blood flow and myocardial ischemia. In:Bonow RO, Mann DL, Zipes DP, Libby P, eds. Braunwald’s Heart Disease. 10th ed. Philadelphia, PA:Elsevier;
2014, pp.1029– 56.
chest patients with low- value FFR lesions is insucient to reduce
ischaemic symptoms and protect against cardiovascular complications. e combination of revascularization (PCI) and optimal
medical treatment produces more favourable results. Conversely,
PCI with so- called bare metal stent placement did not show clinical
benets additional to optimal medical treatment in patients without
low- value FFR lesions., Treatment guidelines by the European
Society of Cardiology recommend to use an FFR threshold of 0.80
to distinguish between coronary stenosis beneting from percutaneous intervention and those which will not. Future studies with
modern stents, including absorbable scaolds, may give rise to a
change in this threshold, and use a higher value. e appropriate
role, if any, of FFR to guide surgical coronary revascularization remains largely undened.
Until recently, FFR measurements were only available invasively
in the interventional laboratory by a catheter- based procedure.
However, due to the recent progress in computer modelling and
computational uid dynamics, minimally invasive coronary imaging procedures by multislice computed tomography (CT) have
also shown good diagnostic clinical results. Performing FFR by
CT angiography also allows assessment of the complete coronary
artery tree in one single examination. is method, called FFRCT,
has been evaluated primarily to see if it improves the diagnostic accuracy of visual coronary stenosis assessment by CT alone. Aer
improvements of the algorithms, FFRCT was also compared against
standard FFR catheter- based methods.
e recent developments in computational uid dynamics- based
FFR methods, also known as virtual FFR, have also been extended
by using input from other coronary imaging methods than CT, such
as rotational angiography, and is sometimes also combined with
intracoronary imaging (intravascular ultrasound and optical coherence tomography) to improve accuracy. However, these methods
require potentially an invasive procedure and the use of agents that
may be uncomfortable when infused to achieve maximum hyperaemia. Furthermore, only a selection of the coronary arteries can be
examined.
Although the rst results of new virtual FFR methods are very
promising, computer modelling of a complex coronary artery
anatomy including diuse diseased vessels with multiple stenoses,
including previously infarcted regions with possible collateral
ow, is a taxing challenge. ese new methods have inherent advantages, certainly when performed minimally or non- invasively,
but it remains to be seen if they are ready to identify complex
lesions.
3.2 Coronary endothelialfunction 13
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REFERENCES
1. Feigl EO. Coronary physiology. Physiol Rev. 1983;63(1):1– 205.
2. Homan JA, Spaan JI. Pressure- ow relations in coronary
circulation. Physiol Rev. 1990;70(2):331– 90.
3. Duncker DJ, Bache RJ. Regulation of coronary blood ow during
exercise. Physiol Rev. 2008;88(3):1009– 86.
4. Canty JM. Coronary pressure- function and steady- state pressureow relations during autoregulation in the unanesthetized dog.
Circ Res. 1988;63(4):821– 36.
5. Duncker DJ, Koller A, Merkus D, Canty JM. Regulation of
coronary blood ow in health and ischemic heart disease. Prog
Cardiovasc Dis. 2015;57(5):409– 22.
6. Homan JI. Transmural myocardial perfusion. Prog Cardiovasc
Dis. 1987;29(6):429– 64.
7. Klocke FJ. Coronary blood ow in man. Prog Cardiovasc Dis.
1976;19(2):117– 66.
8. Kern MJ, Lerman A, Bech JW, De Bruyne B, Eeckhout E, Fearon
WF, etal. Physiological assessment of coronary artery disease
in the cardiac catheterization laboratory:a scientic statement
from the American Heart Association Committee on Diagnostic
and Interventional Cardiac Catheterization, Council on Clinical
Cardiology. Circulation. 2006;114(12):1321– 41.
9. Duncker DJ, Bache RJ. Regulation of coronary vasomotor
tone under normal conditions and during acute myocardial
hypoperfusion. Pharmacol er. 2000;86(1):87– 110.
10. Al- Lamee R, ompson D, Dehbi HM, Sen S, Tang K, Davies
J, etal. Percutaneous coronary intervention in stable angina
(ORBITA):a double- blind, randomised controlled trial. Lancet.
2018;391(10115):31– 40.
11. De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA,
Piroth Z, etal. Fractional ow reserve- guided PCI versus
medical therapy in stable coronary disease. N Engl J Med.
2012;367(11):991– 1001.
12. Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van ’t
Veer M, etal. Fractional ow reserve versus angiography for
guiding percutaneous coronary intervention. N Engl J Med.
2009;360(3):213– 24.
13. Pijls NH, Fearon WF, Tonino PA, Siebert U, Ikeno F, Bornschein
B, etal. Fractional ow reserve versus angiography for guiding
percutaneous coronary intervention in patients with multivessel
coronary artery disease:2- year follow- up of the FAME
(Fractional Flow Reserve versus Angiography for multivessel
Evaluation) study. J Am Coll Cardiol. 2010;56(3):177– 84.
14. Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C,
Budaj A, etal. 2013 ESC guidelines on the management of stable
coronary artery disease:the Task Force on the management
of stable coronary artery disease of the European Society of
Cardiology. Eur Heart J. 2013;34, 2949– 3003.
15. Taylor CA, Fonte TA, Min JK. Computational uid dynamics
applied to cardiac computed tomography for noninvasive
quantication of fractional ow reserve:scientic basis. J Am
Coll Cardiol. 2013;61(22):2233– 4.
16. Koo BK, Erglis A, Doh JH, Daniels DV, Jegere S, Kim HS,
etal. Diagnosis of ischemia- causing coronary stenoses by
noninvasive fractional ow reserve computed from coronary
computed tomographic angiograms. Results from the prospective
multicenter DISCover- FLOW (Diagnosis of Ischemia- Causing
stenoses Obtained via Noninvasive Fractional Flow Reserve)
study. J Am Coll Cardiol. 2011;58(19):1989– 97.
17. Gaur S, Bezerra HG, Lassen JF, Christiansen EH, Tanaka K,
Jensen JM, etal. Fractional ow reserve derived from coronary
CT angiography:variation of repeated analyses. J Cardiovasc
Comput Tomogr. 2014;8(4):307– 14.
18. Tu S, Bourantas CV, Nørgaard BL, Kassab GS, Koo BK,
Reiber JH. Image- based assessment of fractional ow reserve.
EuroIntervention. 2015;11(Suppl V):V50– 4.
19. Davies JE, Cook CM. Is FFRCT ready to assume the crown jewels
of invasive FFR? JACC Cardiovasc Imaging. 2017;10(4):434– 6.
3.2 Coronary endothelialfunction
R. Jay Widmer and Amir Lerman
Coronary endothelialphysiology
e vascular endothelial cell layer functions under basal conditions to maintain the vessel tone, while mitigating inammation,
oxidative stress, and thrombogenicity. e coronary endothelium
regulates blood ow to meet the demands of myocardial oxygen
consumption (VO) by favouring a relatively neutral state in the balance between dilatation and constriction mainly through the action
of nitric oxide (NO) (guanylate cyclase → cyclic guanosine monophosphate), prostacyclin (PGI, cyclic adenosine monophosphate,
platelet aggregation), and shear stress. e endothelial- dependent
vasodilatory response is principally regulated in response to shear
stress by releasing NO synthesized from the amino acid - arginine
by endothelial NO synthase which leads to the production of intracellular cyclic guanosine monophosphate. e vascular wall with
denuded and/ or damaged endothelium may manifest an attenuated
vasodilatory capacity and/ or vasoconstriction to these same physiological or pharmacological substances that would cause a decrease in
tone under normal physiological conditions. Abnormal endothelial
function is attributed to high oxidative stress and inammation—
both processes lead to abnormal NO metabolism (bioavailability,
use/ response, production, release, and degradation), which can be
exacerbated by other conditions (cold, mental stress, anger) that are
known to produce a global vasoconstriction.
Endothelial dysfunction may take place in both epicardial cor-
onary arteries as well as in the coronary microcirculation (Fig.
3.2.1). Epicardial coronary endothelial dysfunction can be detected
in the catheterization laboratory with abnormal vascular responses
to endothelial- dependent physiological or pharmacological stimuli,
and is characteristically a precursor to the initial processes of atherosclerotic coronary disease. In the epicardial coronary arteries,
vascular segments with endothelial dysfunction create favourable
conditions for ongoing inammation, inciting platelet plus leucocyte activation and adhesion, as well as the stimulation of cytokines
that increase the permeability of the vascular wall to oxidized lipoproteins and inammation mediators. Subsequently, pathological
processes involve intraluminal narrowing of the arterial wall with
lipid deposition, smooth muscle cell proliferation/ migration, and
proliferation of the vasa vasorum leading to the formation of vulnerable atherosclerotic plaques detectable via intracoronary imaging
SECTION 1 Pathophysiology and investigation ofcoronary artery disease14
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Plaque
rupture or
erosion
Plaque
progression
ACS
Angina
Coronary
endothelial
dysfunction
Epicardial
endothelial
dysfunction
Microcirculatory
endothelial
dysfunction
Vulnerable
plaque
Myocardial
ischaemia
Cardiomyopathy, diastolic
dysfunction, apical ballooning
Fig.3.2.1 Coronary endothelial dysfunction, both epicardial and microvascular, can produce myocardial ischaemia through obstructive coronary
disease or poor microvascular perfusion globally.
methods including intravascular ultrasound and optical coherence
tomography.– is process produces obstructive coronary artery
disease (CAD), further exacerbating a myocardial oxygen supply/
demand mismatch, thus causing further inammation, plaque progression, and potentially acute coronary syndromes. Moreover, epi-
non- obstructive CAD.– Studies report the majority of these patients demonstrate endothelial dysfunction.,, us, it may be
speculated that the majority of the patients presenting for coronary
angiogram with non- obstructive CAD will have evidence of ab-
normal coronary physiology and endothelial dysfunction.
cardial vessels with endothelial dysfunction have the propensity
for vasoconstriction, further aggravating myocardial ischaemia.
Resultantly, these active and evolving progressive lesions can pro-
Evaluating coronary endothelialfunction
gress to an erosive state or even frank plaque rupture manifesting in
acute coronary syndromes. us, the initial transformation of the
endothelial layer to an abnormal state is paramount in predicting
future cardiovascular disease, and should be investigated in those
suspected of having or at risk for CAD.
Abnormal endothelial function can also occur in the coronary
microcirculation, either separately or in concert with epicardial
endothelial disease (Fig. 3.2.1). Oen, microcirculatory abnormalities precede epicardial disease, and can be used to predict the
initiation of obstructive epicardial disease. e presence of endothelial dysfunction in the microcirculation attenuates the vasodilation in response to increased demands such as exercise or mental
stress leading to myocardial ischaemia. ese repetitive diminutive
ischaemic events may lead to cardiomyopathic processes such as
apical ballooning or heart failure with preserved ejection fraction
(Fig. 3.2.1).
Functional coronary angiography should be used to directly and
invasively examine coronary endothelial function. e guiding
principle in evaluating coronary endothelial function is the assessment of the changes in coronary artery diameter and coronary
blood ow in response to physiological (exercise, mental stress) or
endothelium- dependent vasodilatory pharmacological (acetylcholine, bradykinin) stimuli of the endothelium., For practical use,
the intracoronary administration of acetylcholine has become the
gold standard for these evaluations. In healthy coronary epicardial
and microvascular vessels, acetylcholine generates an NO- mediated
vasodilatory response leading to an increase in coronary epicardial diameter and an increase in coronary blood ow as assessed
by intracoronary Doppler. In patients with endothelial dysfunction,
this eect is blunted or even paradoxically causes vasoconstriction.
Non- invasive tests for assessment of coronary endothelial function
include Doppler echocardiography, positron emission tomography,
Endothelial dysfunctionprevalence
and phase- contrast magnetic resonance imaging.
Coronary blood ow can be calculated from measurements of
coronary ow velocity and coronary cross- sectional area with the
e true prevalence of coronary endothelial dysfunction is not fully
known since it is highly dependent upon the referral bias. However,
previous observations demonstrate that 40– 60% of patients undergoing clinically indicated coronary angiography are found to have
hydraulic equation (ow=velocity × area). Diagnostic angiography
including measures of Doppler velocity and vessel diameter is per-
formed with each graded increase in acetylcholine dose (Fig. 3.2.2).
In patients with endothelial dysfunction, acetylcholine is ineective
Functional angiogram protocol
Post-ACh vasospasm
Diagnostic
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angiography
IC ACh
–4
10
10
3.2 Coronary endothelialfunction 15
diabetes mellitus, metabolic syndrome, and hypertension would be
Microcirculation
–6
pre-ACh, APV
74
240
179
85
100
50 50 5
120
expected to improve vascular function. Pharmacological therapy
with statins and angiotensin- converting enzyme inhibitors has been
shown to improve endothelial dysfunction. e addition of vasodilators such as nitrates for epicardial endothelial dysfunction and
calcium channel blockers for both epicardial and microvascular
endothelial dysfunction also has become common practice. e role
of experimental NO donors, such as phosphodiesterase inhibitors,
Post-ACh APV
57
240
170
100
050105
120
sh oils, and antioxidants, is mostly anecdotal. e search for nonconventional risk factors such as sleep disorders and/ or inammatory processes is also recommended. It is notable that patients with
endothelial dysfunction who do not respond positively to therapies
demonstrate much worse clinical outcomes.
Conclusion
Fig.3.2.2 After diagnostic angiography, intracoronary (IC) acetylcholine
(ACh) at increasing doses is administered with simultaneous
measurement of diameter (angiogram, left) and velocity (average peak
velocity (APV), right). Normal segment with only mild eccentric plaque
seen by intravascular ultrasound (middle bottom).
e assessment of coronary endothelial function has profound importance in terms of diagnostic and prognostic signicance in patients with both obstructive and non- obstructive CAD. ere are
various methods used in diagnosis; however, the most commonly
used and accepted practice remains invasive functional coronary
in releasing NO and may mediate coronary vasoconstriction. Aless
than 20% increase in coronary arterial diameter is formally classied as epicardial endothelial dysfunction. Abnormal microcirculatory endothelial function is present if coronary blood ow does not
angiography using acetylcholine, which normally functions as an
endothelium dependent vasodilator. ese measures can provide
the diagnosis of coronary endothelial dysfunction, as well as guide
treatment strategies and prognosis.
increase by greater than 50% from baseline.,,
Prognosis
In patients without obstructive CAD but impaired coronary endothelial function there is a marked increase in cardiac events, including stroke, over the following 2 years.– is notion was
furthered in a similar observation following patients for nearly
8years showing a 20– 40% reduction in survival over the subsequent 7.7years depending on their coronary vascular reactivity
to any certain number of stimuli. Astudy in patients with CAD
showed that persistent impairment of endothelial vasomotor function despite optimized therapy to reduce risk factors has an adverse
impact on clinical outcome.
Endothelial dysfunction is a systemic disorder and may involve multiple vascular beds. Indeed, both peripheral endothelial dysfunction,
as measured by ow- mediated dilation,, and microvascular endothelial dysfunction,, have been found to be independent predictors
of future cardiovascular events in large cohort studies in healthy individuals over and above traditional risk factor assessment. Endothelial
dysfunction appears to be related to baseline risk factors, thus making
it an attractive alternative metric in secondary prevention.
ere are currently no guideline- based therapies for coronary
endothelial function. However, most of the interventions that were
shown to improve endothelial function are also associated with a reduction in cardiovascular events. Taking into account the association
of endothelial dysfunction with conventional and non- conventional
risk factors, the rst line of treatment is aggressive lifestyle and
risk factor modication including aerobic exercise, weight loss in
obese patients, low- fat or Mediterranean diets, and smoking cessa-
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Coronary endothelial dysfunction in humans is associated with
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(Tako- Tsubo or stress cardiomyopathy):a mimic of acute
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9. Sara J, Widmer RJ, Matsuzawa Y, Lennon RJ, Lerman LO, Lerman
A. Prevalence of coronary microvascular dysfunction among
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10. Ong P, Athanasiadis A, Hill S, Vogelsberg H, Voehringer M,
Sechtem U. Coronary artery spasm as a frequent cause of acute
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Cali RM, etal. Prognostic implications of abnormalities in renal
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17. Flammer A, Anderson T, Celermajer DS, Creager MA, Deaneld
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18. Lerman A, Zeiher AM. Endothelial function:cardiac events.
Circulation. 2005;111(3):363– 8.
19. Shechter M, Sherer Y. Endothelial dysfunction:a crystal ball
prediction for enhanced cardiovascular risk? Isr Med Assoc J.
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20. Schächinger V, Britten MB, Zeiher AM. Prognostic impact of
coronary vasodilator dysfunction on adverse long- term outcome
of coronary heart disease. Circulation. 2000;101(16):1899– 906.
21. Kitta Y, Obata JE, Nakamura T, Hirano M, Kodama Y, Fujioka D,
etal. Persistent impairment of endothelial vasomotor function
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22. Huang A, Silver AE, Shvenke E, Schopfer DW, Jahangir E, Titas MA,
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24. Anderson T, Charbonneau F, Title LM, Buithieu J, Rose
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A, MacIsaac A, etal. e resting status of the coronary
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3.3 Coronary arteryspasm
Hiroaki Shimokawa and Jun Takahashi
Coronary artery spasm is a condition in which an epicardial coronary artery or coronary bypass gra exhibits abnormal transient
constriction with possible or subsequent development of myocardial ischaemia and/ or sudden cardiac death. Coronary spasm plays
a key role in the pathogenesis of a wide range of ischaemic heart
diseases, including not only variant angina but also eort angina,
acute myocardial infarction, and sudden cardiac death. Although
coronary spasm has been believed to be more prevalent in Asian
compared with Caucasian populations, a study in 2014 suggested
that the prevalence of coronary spasm is comparable between the
two groups. us, coronary spasm is a global issue. Coronary artery spasm frequently occurs at angiographically atherosclerotic
lesions of the coronary artery. Even when no stenotic lesions are
noted on coronary angiography, intravascular ultrasound oen
shows the presence of arteriosclerotic lesions in the spastic coronary
segment.
We rst developed a porcine model of coronary atherosclerosis through a combination of balloon endothelial injury/ removal
and high- cholesterol feeding, in which we examined the coronary
vasoconstricting responses to various agonists in vivo. Although
the degree of the atherosclerotic lesion was too mild to be detected
angiographically, intracoronary administration of serotonin or histamine repeatedly induced coronary spasm at the atherosclerotic
lesions, where there was a close topological correlation between
the spastic site and atherosclerotic lesion. (Fig. 3.3.1a,b). ese
results provided the rst experimental evidence for the close relationship between coronary spasm and coronary atherosclerosis.
Subsequently, it was demonstrated that sudden onset and/ or severe
coronary spasm could induce sudden progression of angiographic
coronary stenosis due to intramural haemorrhage and mural
thrombus formation secondary to atherosclerotic plaque erosion.,
It was previously reported that inammatory changes of the adventitia of the coronary artery were associated with both coronary
spasm and atherosclerosis. us, we developed the second porcine
model of spasm, in which we created a coronary adventitial inammatory lesion with interleukin- 1 beta (IL- 1β) and conrmed the
occurrence of coronary vasospastic abnormalities. Histological
examination showed the accumulation of inammatory cells at
the adventitia, mild neointimal formation, and a reduction in vascular cross- sectional area (negative remodelling) (Fig. 3.3.1c,d).
IL-1β beads Control beads No treatment
23
(a)
(b)
(c)
(d)
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(a)
(b) (c)
Control
8
9
71
Nitroglycerin Serotonin
Histamine Serotonin
3.3 Coronary arteryspasm 17
hypercontraction of vascular smooth muscle cells, but not endothelial dysfunction.
Subsequently, we demonstrated that activation of Rho- kinase, a
molecular switch of vascular smooth muscle contraction, plays a central molecular mechanism for the development of spasm, rst in the
porcine model and later in patients with vasospastic angina as well.
We also demonstrated that fasudil, which is used for the treatment
of cerebral vasospasm aer subarachnoid haemorrhage in Japan, is
metabolized to hydroxyfasudil, which acts as a selective Rho- kinase
inhibitor in multiple vascular beds in humans. More recent studies
demonstrated that inammatory changes in the adventitia of the cor-
4
onary artery play an important role for Rho- kinase activation through
vasa vasorum formation and increased perivascular adipose tissue.
Repeated episodes of coronary spasm may injure the vascular wall,
5
accelerating the progression of coronary atherosclerosis. Indeed, the
locations of coronary spasm are susceptible to atherosclerosis, and
suppression of vasospastic activity may lead to regression of coronary
atherosclerosis. Coronary spasm is one of the causes of rupture of
6
vulnerable coronary plaques. Reduced blood ow due to coronary
spasm activates platelets and the coagulation system, promoting
atherosclerosis. Prevention and treatment of coronary spasm is
important in preventing acute coronary syndromes and sudden
cardiac death.
(a) (b) (c)
Fig.3.3.1 Coronary artery spasm provoked in two porcine models in
vivo. Coronary artery spasm was provoked in atherosclerotic miniature
pigs induced by balloon endothelial injury and high- cholesterol feeding
(a), where topological correlation was noted between the spastic
sites and the early atherosclerotic lesions (b). Coronary artery spasm
was provoked in pigs with adventitial inflammation (c), where intimal
thickening and negative remodelling were noted (d).
Reproduced from Shimokawa, H.2014. 2014 Williams Harvey Lecture:importance of
coronary vasomotion abnormalities— from bench to bedside. Eur Heart J, 35, 3180– 93
with permission from Oxford University Press.
Moreover, smooth muscle phenotype was altered towards dedifferentiation at the spastic site. ese vascular eects were not specic for IL- 1β because the same treatment with other inammatory
cytokines, such as IL- 1α and tumour necrosis factor alpha, also induced the same histological and functional alterations of the porcine
coronary artery. ese results indicate that among the pathological
components of atherosclerosis, inammatory adventitial changes of
the coronary artery play a pivotal role in the pathogenesis of spasm.
is second porcine model without endothelial injury/ removal
demonstrated that the central mechanism of coronary spasm is
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