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Current Pharmaceutical Design, 2013, 19, 1593-1600 1593

Insight to the Pathophysiology of Stable Angina Pectoris

Dimitris Tousoulis*, Emmanuel Androulakis, Anna Kontogeorgou, Nikolaos Papageorgiou, Marietta

Charakida, Katerina Siama, George Latsios, Gerasimos Siasos, Anna-Maria Kampoli, Panagiotis Tourikis,
Kostas Tsioufis and Christodoulos Stefanadis

1st Cardiology Department, Hippokration Hospital, Athens University Medical School, Greece

Abstract: Atherosclerosis is a chronic disease which mainly represents an inflammatory response in the vessels. Myocardial ischemia
manifested by angina pectoris can be either acute or chronic and usually is a result of imbalance between myocardial oxygen supply and
myocardial oxygen demand. Chronic stable angina is chest discomfort attributed to myocardial ischemia without the presence of necrosis
and is the most common symptom encountered by emergency room physicians. A growing amount of data has shown that endothelial
dysfunction, is now considered an important early event in the development of atherosclerosis, while in the absence of angiographically
obstructive coronary artery disease, anginal chest pain is often attributed to microvascular coronary dysfunction. Moreover, atheroma
formation and in turn, atherosclerotic plaques seem to affect coronary flow, given that multivessel flow-limiting obstructions are ob-
served in patients with chronic coronary syndrome. Morphological changes of diseased arteries related to significant atherosclerosis, such
as vascular remodeling may also result in stable angina or claudication. However, several issues with respect to the comprehension of the
pathophysiology of the chronic coronary syndrome have not been fully elucidated.
Keywords: Stable angina, atherosclerosis, pathophysiology, myocardial ischemia.

INTRODUCTION GENERAL CONSIDERATIONS

Atherosclerosis is a chronic disease which represents in large Cardiac ischemia is the consequence of an imbalance between
part, an inflammatory response in the vessels [1, 2]. The pathogene- myocardial oxygen supply and demand. In general, the reduction in
sis of atherosclerosis includes complex processes leading to the coronary blood flow (CBF) results in development of an acute
formation of atherosclerotic plaque [3]. Of note, during the last coronary syndrome (ACS). It is well-defined that angina pectoris
decade, it has become evident an interplay of genetics and inflam- constitutes a heaviness or pressure retrosternally, with possible
mation which leads to a greater understanding of the complex radiation to the ulnar aspect of both arms, shoulders, neck, jaw and
pathophysiology of atherosclerotic vascular disease [4]. mid-abdomen with an average frequency of 2 attacks per week [11].
According to large scale studies 85-90% of patients with coro- Since myocytes consume most of the oxygen supplies in coronary
nary artery disease (CAD) have traditional risk factors such as hy- blood at rest, in state of a higher demand CBF is increased [12].
pertension, smoking and diabetes mellitus, however, considerable Regarding the sensation of pain, several mediators such as lactate
data have shown that atherosclerosis and CAD are preventable dis- are produced, as a result of hypoxia which disrupts oxidative meta-
eases [5, 6]. Growing evidence has shown that endothelial dysfunc- bolic pathways [13].
tion (ED), is now considered an important early event in the devel- Cardiac ischemia seems to be subdivided into two clinical phe-
opment of atherosclerosis. Also, it seems possible to precede athe- notypes; ACS and CCS. In particular, an acute reduction in CBF
rosclerotic lesions in both conduit and coronary vessels, and even and hence, myocardial oxygen supply, is usually the mechanism of
occur in offspring with a positive history for cardiovascular disease ACS. In this case, recent events including rupture, erosion and
[7-9]. hemorrhage often superimposed on thrombosis and/or microem-
Anginal chest pain is the most common symptom encountered bolism reduce CBF and lead to acute ischemic myocyte injury [14].
by emergency room physicians. Angina is chest discomfort as a In contrast, a sudden increase in oxygen demand, in the ground of
result of myocardial ischemia without the presence of necrosis, and disability of the myocardium to meet that demand, is usually the
is further divided according to several factors and clinical character- mechanism of ischemia in the CCS. In those patients, the ischemia
istics. Typical angina may be triggered by increased activity, emo- is transient and without evidence of myocyte injury. Life-
tional stress or other stressful stimuli, such as cold and fever. Over threatening arrhythmias may occur in both cases but more fre-
the last decades, despite the considerable advances regarding the quently after reperfusion in ACS [11].
pathophysiology of ischemic heart disease (IHD), the comprehen-
Types of Angina
sion of the pathophysiology of the chronic coronary syndrome
(CCS) has not been fully elucidated [10]. • Chronic stable angina is caused in the basis of one or more
significant obstructive lesions in coronary arteries (
50 of the
In the present chapter we will discuss recent data regarding to
left main coronary artery or
70% of a major epicardial ves-
the pathogenetic mechanisms of atherosclerosis, chronic IHD and
sel).
hence, the pathophysiology of chronic stable angina, providing
clues for prevention strategies that could lead to approaches related • Refractory stable chronic angina is defined in case where it
to the management of the growing number of patients with CSS. is not controllable by a combination of maximal anti-anginal
medication, angioplasty or coronary artery bypass surgery
[15].
*Address correspondence to this author at the Athens University Medical
School, Hippokration Hospital, Vasilissis Sofias 114, 115 28, Athens, • Unstable angina (UA), occurs at rest or after minimal physi-
Greece; Tel: +302107782446; Fax: +302107485039; cal activity lasting over 10 min, and/or angina with a cres-
E-mail: drtousoulis@hotmail.com cendo pattern, which is a more severe, of greater duration and
less responsive to nitroglycerin. Unstable angina is an ACS.

1873-4286/13 $58.00+.00 © 2013 Bentham Science Publishers

1594 Current Pharmaceutical Design, 2013, Vol. 19, No. 9 Tousoulis et al.

In case of elevated myocardial enzymes, such as troponin I Table 1. Diagnostic Approaches for Chronic Stable Angina
and troponin T, the applicable clinical term becomes non-ST-
elevation myocardial infarction (NSTEMI).
Method Comments
• Syndrome X is typically more common in women, is accom-
panied by normal coronary angiograms, and positive exercise Electrocardiogram Low sensitivity- resting ECG may be
tests, while endothelial dysfunction potentially is a critical normal in 50% of patients
pathophysiological suspect.
• Vasospastic or Prinzmental’s angina occurs at rest, often at Exercise treadmill Moderate sensitivity and specificity. Initial
night and is due to focal vasospasm of an epicardial coronary testing non-invasive test for risk stratification and
artery, rather than atherosclerotic lesions. It is characterized diagnosis of CAD
either by transient elevation in ST-segments on the electro-
cardiogram or ST depression [16]. Stress imaging Preferred in patients with a history of prior
revascularization
Diagnosis (Table 1)
Stress It is limited by patient characteristics
Interestingly, a large proportion of the patients who are seen in
emergency rooms (about 50-55%), are diagnosed with non-cardiac Echocardiography (obesity, chronic obstructive pulmonary
chest pain [17]. Diagnosis of cardiac chest pain relies on history, disease)
patient characteristics, and identification of classical risk factors. It Stress myocardial Preferred in women and obese patients
has been indicated that high risk patients would benefit more from
perfusion
coronary angiography rather than non-invasive testing, whereas in
case of a low probability of having CAD, further work up should Cardiac magnetic Able to detect and quantify areas of
focus on non-cardiac causes of pain [18]. The electrocardiogram resonance imaging necrosis and scar tissue. Limited in patients
(ECG) is a convenient, though insensitive method of diagnosing
with metallic hardware
myocardial ischemia. A resting ECG is often normal in stable an-
gina pectoris in the absence of a previous MI, while during pain the Computed tomography Coronary artery calcification can be
ECG could show ST- segment depression and/or T wave inversion. determined. May be useful in the coronary
Also, exercise treadmill testing is recommended for the initial non- artery lumen and plaque visualization
invasive risk stratification and diagnosis of CAD in patients who
are capable of exercising and negative ECG. However, the gold Positron emission High sensitivity and contrast resolution.
standard for definitive diagnosis of CAD remains invasive coronary tomography Able to detect ischemia accurately
angiography which indicates the site and severity of a coronary
lesion, especially in patients with absolute contraindications to Coronary angiography Gold standard for definitive diagnosis of
stress testing, or medically refractory angina [19]. Functional ca- coronary artery disease
pacity classification and exercise capability in angina patients are
presented in Table 2. Angina must be differentiated from other
well-known causes of chest pain, such as gastrointestinal, muscu- Table 2. Functional Capacity Classification and Exercise
loskeletal and pulmonary causes. Capability in Angina Patients

MECHANISMS RELATED TO THE PATHOPHYSIOLOGY

OF ATHEROSCLEROSIS Class Activity level Exercise toler-
ance-METs
Endothelial Dysfunction
Endothelium is a semi permeable barrier between blood and the Class I (Minimal Ordinary physical activity 7-8
underlying tissue that lines the entire cardiovascular system while is limitation) does not cause angina
also a key regulator of vascular tone [20], blood coagulation [21],
angiogenesis [22], immunity and inflammation. Endothelial cells Class II (Mild Slight limitation of physical 5-6
(ECs) ensure vascular homeostasis by secreting various vasoactive limitation) activity
molecules (nitric oxide, prostacyclin, endothelin), antithrombotic
substances (tissue type plasminogen activator-tPA, von willebrand Class III (Severe Marked limitation of physical 3-4
factor-vWF, plasminogen inhibitor activator-1-PAI-1) [21], growth limitation) activity
factors (vascular endothelial growth factor) [22], cytokines and
Class IV Severe limitation. Physical 1-2
other mediators [23]. Thereby, proper endothelial function provides
vascular health by coordinating vascular smooth muscle cells (Extreme limita- activity is always
(VSMC), platelets and peripheral leukocytes activity through the tion) accompanied by discomfort
respective mediators. However, under certain and thoroughly stud-
ied circumstances endothelial function is impaired thus triggering
Traditional risk factors including diabetes mellitus, smoking, hyper-
atherogenic processes [24-26]. Nitric oxide (NO) is a potent endo-
tension, hyperlipidemia and hyperhomocysteinemia down regulate
thelial molecule that mediates the majority of atherosclerotic altera-
endothelial nitric oxide synthase (eNOS) activity and favor reactive
tions. NO is an endogenous anti-atherogenic molecule which exhib-
oxygen species (ROS) formation [31-33]. The subsequent reduced
its vasodilatory properties [27], as well as anti-thrombotic, anti-
NO bioavailability predisposes to atherosclerosis [34-36] through
inflammatory [28] and anti-oxidant activity [29, 30]. When ade-
various mechanisms including the upregulation of adhesion mole-
quate, NO prevents the abnormal vasoconstriction and inhibits the
cules (intercellular adhesion molecule-1, vascular cell adhesion
overexpression of pro-inflammatory cytokines and adhesive mole-
protein-1, P-selectin, E-selectin, vWf) [37] and the enhanced circu-
cules. Obviously, NO deficiency results in platelet aggregation,
lation of inflammatory mediators (interleukins-IL, tumor necrosis
sub-endothelial accumulation of leukocytes and smooth cell prolif-
factor-a-TNF-a) [38]. Indeed, the atherosclerotic procedures are
eration which are initial and essential incidents in atherogenesis.
mostly NO-depended. Particularly, NO production inhibits the
Pathophysiology of Stable Angina Pectoris Current Pharmaceutical Design, 2013, Vol. 19, No. 9 1595

formation of the vasoconstrictor endothelin-1 (ET-1) secreted by systemic oxidative stress and thus damage proper endothelial func-
ECs which is mainly found increased in states of endothelial dys- tion [55-58]. NO bioavailability is typically damaged as a result of
function and atherosclerosis [39, 40]. Furthermore, NO regulates eNOS gene down regulation [59] and enhanced reactive oxygen
the secretion of vWf, PAI-1, TNF-a and IL-1 which in states of species generation. NO is the most well-identified endothelial
endothelial injury increase and result in leukocyte migration and molecule that exhibits vasculoprotective properties. Obviously,
platelet aggregation. Additionally, NO exhibits antioxidant proper- reduced NO release predisposes to atheromatous disease. Particu-
ties by scavenging free radicals. Experimental studies suggest that larly, insulin itself is a well established stimulant of eNOS activity.
reduced NO is associated to O2- accumulation and subsequent to In states of DM, insulin deficiency triggers pathophysiological al-
potent reactive oxygen metabolites formation [41]. Free radicals terations that result in impaired NO bioavailability [60-62]. Be-
either directly consume NO or down regulate eNOS activity thus sides, insulin resistance activates the mitogen-activated protein
diminishing NO bioavailability and maintaining the vicious circle kinase (MARK) via the GTPase Ras (Ras/MARK pathway) and
of oxidation [42-44]. Consequently, endothelial dysfunction and the results in enhanced expression of the vasoconstrictor ET-1 as well
concomitant alterations are the initial step of atherosclerotic disease as pro-inflammatory adhesion molecules [63, 64]. Furthermore, the
and related clinical manifestations. up regulation of NADPH oxidase [65, 66] in combination with the
uncoupled eNOS activity favor the enhanced ROS generation [67].
Microvascular Dysfunction Specifically, ROS damage vascular health through directly consum-
In the absence of angiographically obstructive CAD, anginal ing NO and simultaneously favor the augmented excretion of endo-
chest pain is often attributed to microvascular coronary dysfunction. thelium-depended contracting factors [68, 69]. Additionally, endo-
It can be observed impaired dilation from ED at both macro and thelial progenitor cells (EPCs) are currently implied in the patho-
microvascular levels which may contribute to limit blood flow [19]. physiology of diabetic vasculopathy [70, 71]. EPCs are stem cells
Histologic evidence for small-vessel coronary artery disease in originating from bone marrow that are implicated in mechanisms of
patients with angina pectoris in patients with normal angiograms vascular repair. DM damages the quantity and quality of EPCs with
has revealed myointimal proliferation, endothelial degeneration, the proportionate consequences for blood vessels.
and lipid deposits in the microvasculature, while accumulating evi- Hyperlipidemia is characterized by elevated circulating levels
dence involve coronary microcirculation dysfunction in IHD [45]. of LDL which impair vascular homeostasis. The modification of
In that case, risk factors (hypertension, dyslipidemia, obesity, dia- LDL in the respective oxLDL seems to be the key mechanism to
betes etc.) also contribute to increased oxidant stress within endo- that process [72-74]. Hyperlipidemia reduces NO bioavailability
thelial cells to impair nitric oxide bioavailability. Moreover, similar and mobilizes inflammatory processes [75]. Specifically, hypercho-
to other cardiovascular diseases, patients with angina pectoris and lesterolemia favors leukocyte and platelet adhesion as it enhances
microvascular dysfunction usually are presented with elevated lev- the circulation of pro-inflammatory adhesion molecules [76]. Addi-
els of inflammatory biomarkers, such as C-reactive protein, sug- tionally, several experimental trials prove a remarkable increase of
gesting an underlying inflammatory process [46]. Recently, vascu- the vasoconstrictor ET-1 [77, 78]. Furthermore, essential hyperten-
lar endothelium has emerged as a potential therapeutic target, hence sion has been demonstrated to be accompanied by both increased
dilation of coronary resistance arterioles in CCS is under current basal vascular resistance and abnormal induced vasodilatatory re-
investigation [47, 48]. sponse to acetylcholine, reflecting an endothelium-derived NO
system defect. Several data have suggested that ED in hypertension
Inflammation and Oxidative Stress in Atherosclerosis could be attributed to a selective abnormality of NO synthesis,
Atherosclerosis is a disease of large and medium sized arteries probably related to impaired intracellular phosphatidilinositol/Ca2+
that covers a broad spectrum of clinical manifestations such as pathway [49]. Importantly, recent evidence has shown that systemic
CAD. The formation of atheromatous plaque is the resultant of inflammation and infections may participate in the initiation and
multiple incidences including endothelial dysfunction, systemic evolution of CAD, given the potential role of mast cells, neutrophils
inflammation, dyslipidemia and impaired immunology [49]. Diabe- and dendritic cells along with the presence of macrophages and T
tes mellitus (DM), hypertension, smoking and hyperlipidemia are lymphocytes in atherosclerotic lesions [49]. For example, among
the most well-clarified incriminating risk factors which damage various mechanisms, viral and bacterial infections have been found
endothelial homeostasis in multiple ways. to be involved in the development and progress of atherosclerosis
Clinical and experimental studies have investigated the se- by triggering several inflammatory processes which lead to the
quences of pathophysiological alterations that lead to the formation expression of pro-inflammatory cytokines and adhesion molecules,
of atheromatous plaque. Specifically, the concomitant endothelial migration and differentiation of smooth muscle cells [49, 51, 52].
dysfunction triggers the enhanced circulation of pro-inflammatory
cytokines and growth factors [50, 51]. Under those conditions, cir- THE ATHEROSCLEROTIC PLAQUE
culating immune cells (leukocytes, monocytes, lemphocytes) attach Furthermore, macrophages at this stage metabolise cholesterole
to the vessel wall while VSMCs under the influence of growth and and modify to foam cells. The foam cells’ interactions with other
chemotactic factors migrate and proliferate within the intima [52]. cells, such as T lymphocytes, form fatty bands, leading to the de-
Furthermore, low density lipoproteins (LDL) and cholesterol build velopment of the subendothelial lipid core, which is one of the most
up within the intima and thus the vessel wall progressively thickens. important stages of the progress of a vulnerable plaque [79]. A
Additionally, secluded from blood antioxidants, LDL are modified growing body of data has identified several molecular and cellular
to oxidized forms (oxLDL) which contribute to the formation of the processes causing the atherosclerotic plaques and progressing to a
atheromatous plaque in two ways. On one hand, oxLDL triggers vulnerable plaque in which, subclinical inflammation seem to play
systemic inflammatory response with the aforementioned resultants crucial role [4]. Atheroma formation and in turn, atherosclerotic
[53]. In addition, macrophages that have previously migrated into plaques seem to affect coronary flow, given that multivessel flow-
the vessel wall undertake oxLDL and transform into foam cells limiting obstructions which are observed in patients with CCS.
[54]. Apparently, inflammatory and oxidative mechanisms are Even though, vulnerable plaques (rupture, erosions, intraplaque
dominant in pathophysiology of atherosclerosis and are triggered by hemorrhages) are considered the pathophysiological substrate of
multiple risk factors analyzed below. ACS, the mechanisms responsible for the evolution of CCS are not
DM is a major risk factor that contributes multifactorily in the elucidated yet [80].
emergence and progression of the atherosclerotic disease. Hyper-
glycemia, insulin resistance and elevated free fatty acids result in
1596 Current Pharmaceutical Design, 2013, Vol. 19, No. 9 Tousoulis et al.

It is well-known that lipid core formation is accompanied by several stages, such as gene transcription, and the inhibition of the
smooth muscle cell migration and proliferation leading to the pro- active enzyme by endogenous inhibitors. A2-macroglobulin and
duction of collagen and other extracellular matrix proteins (elastin, tissue inhibitors of metalloproteinases (TIMPs) normally regulate
proteoglycans), which provide mechanical strength. Actually, ma- MMPs, while disruption of the balance between the MMPs’ pro-
trix metalloproteinases (MMPs), a family of zinc metallo-endopep- duction and their inhibition may result in uncontrolled ECM poduc-
tidases, seem to be involved in all stages of the atherosclerotic tion and remodeling observed in several cardiovascular diseases
process, from the initial lesion to plaque rupture. Also, it has been [94].
recently suggested that MMP activity may facilitate atherosclerosis, Matrix metalloproteinases and their inhibitors, as well as the
plaque destabilization, and platelet aggregation [81, 82]. Advanced interactions among arterial wall components, determine a major
plaques tend to present with large lipid cores in which the extracel- part of arterial mechanical properties in cardiovascular diseases. For
lular matrix has been extensively degraded. These lesions also con- example, patients with essential hypertension exhibit predominantly
sist of a fibrous cap probably attributable to dysfunctional or apop- eutrophic inward remodeling (small arteries), while in secondary
totic smooth muscle cells. Activated macrophages in the atheroscle- hypertension hypertrophic remodeling is mostly being observed
rotic plaque may induce collagen breakdown in the fibrous cap by [95]. More specifically, a significant contributor to the development
MMPs, thus contributing to the vulnerability of plaques to rupture of atherosclerotic lesions is circulating inflammatory cells. Even
[82, 83]. Smooth muscle cell dysfunction is stimulated by macro- though, the underlying mechanisms allowing for leukocyte after the
phages via several mechanisms including the production of nitric adhesion event remain largely unknown, it has been recently sug-
oxide, pro-inflammatory cytokines. Moreover, it has been shown in gested that MMP action may facilitate these processes [96]. It has
previous studies that macrophages participate at the eventual rup- been demonstrated that interactions between T lymphocytes and
ture of a thin fibrous cap, given the fact that plaques usually rupture endothelial cells potentially trigger T-cell secretion of MMP-2,
at sites of increased macrophage content [81]. which degrades basement membrane [97]. In turn, infiltrating cells
Plaque rupture may occur rapidly or gradually and, unstable interact with ECM, oxidized lipids, and with each other which lead
plaques often rupture at the plaque shoulder, where T lymphocytes in production of MMPs in macrophages and further structural
and macrophages are more common than smooth-muscle cells [83]. changes [96].
Eventually, rupture of the fibrous cap releases lipids, inflammatory Furthermore, given its role as a potent vasoconstrictor but also
cells, tissue factor, necrotic debris, and platelet derived prothrom- as an inflammation mediator and a promoter of cell growth, matrix
botic substances to the circulation, provoking the platelet activation deposition and prothrombotic state, angiotensin II is considered a
and aggregation and thrombosis. Accumulating evidence also sug- regulatory factor in the changes in wall structure and function dur-
gest that increased density of vasa vasorum is present in lesions ing vascular remodeling. Although several angiotensin receptors
with increased inflammatory activation and intraplaque hemor- have been described, type 1 (AT1) receptor potentially plays crucial
rhage, suggesting that these microvessels contribute to plaque pro- role on the physiological and pathological effects during vascular
gression [84]. Furthermore, systemic factors may influence local remodeling. The AT1 receptor signals through small GTP-binding
plaque instability and this is nicely exemplified by data which have proteins which stimulate several signaling cascades, leading in tis-
shown that high-sensitivity C-reactive protein level is independ- sue remodeling via induction of SMC hypertrophy, hyperplasia, and
ently related to increased risk of acute coronary event. Of note, migration and extracellular matrix production [98].
several biomarkers implicated in the pathogenesis of atherosclerosis
and its complications have emerged as potent biomarkers for early Recently, differences in vascular remodeling have been ob-
detection of myocardial ischemia [85, 86]. served related to variations in SMC phenotype. In particular, they
may be appeared in several states, such as decreased, apoptotic, or
VASCULAR REMODELING AND ARTERIAL STIFFNESS dysfunctional in terms of synthesis and repair of extracellular ma-
IN ATHEROSCLEROSIS trix [99]. Obviously, morphological changes of diseased arteries
related to significant atherosclerosis include progressive flow-
Vascular remodeling is considered as any change in the size
limiting stenosis and result in stable angina or claudication. Recent
and/or composition of the vessels in the ground of adaptation and
advances in clinical imaging have led to the observation that while
repair. Moreover, homeostasis of the vascular extracellular matrix
atherosclerotic lesions develop within the intimal layer, the whole
(ECM) may affect structural and functional properties of the arterial
arterial wall is reshaped resulting in different geometrical patterns.
wall, such as vascular remodeling and arterial elasticity [87]. Al-
Therefore, vascular remodeling can be expansive, also known as
terations in hemodynamic forces including luminal pressure and
positive (compensatory) remodeling, which is observed more often
shear stress, either physiological or pathological, lead to functional
and to a greater degree in ACS than in CCS [100]. Otherwise, it can
and/or structural alterations of the vascular wall including changes
be constrictive, also known as negative remodeling which occurs in
in wall diameter and thickness. However, these changes are not
most patients with a CCS and a few patients with an ACS presenta-
solely determined by hemodynamic forces, and a role for inflamma-
tion [99]. These later considerations have shifted current concept of
tory responses and changes in ECM components has been sug-
atherosclerosis and have provided a framework for understanding
gested [88, 89].
current pathophyiological determinants of ACS and stable angina.
The ECM in the vascular has a supporting and structural role
Large-artery stiffness due to alterations in ECM, is an inde-
and its function (elasticity, resistance to stretch) depends for the
pendent predictor for cardiovascular morbidity and mortality, re-
most part on collagens and elastin, the main protein constituents of
sponsible for increased peripheral resistance and is the main deter-
vessels [90]. Moreover, proteoglycans and structural glycoproteins,
minant of pulse pressure. Aortic stiffness can be estimated directly
which are synthesized by the three vascular cell types: intimal en-
by assessing pulse wave velocity (PWV) along the descending
dothelial cells, medial smooth muscle cells and adventitial fibro-
aorta, using appropriate software [101]. Notably, increased arterial
blasts, play crucial roles in other functions of vessels, while colla-
stiffness and wave reflection amplitude are associated with in-
gen types I and III represent 60% and 30% of vascular collagens,
creased systolic aortic pressure and pulse pressure as well as myo-
respectively [91, 92]. Moreover, metalloproteinases are endopepti-
cardial systolic wall stress and oxygen demand [102]. With regards
dases that physiologically participate to tissue remodeling in several
to its relation to MMPs and ECM alterations, it has been observed
physiological processes. In contrast, they are enzymes that degrade
increased MMP-9 activity in state of hypertension, whereas in an
the ECM, contribute to the physiological remodeling after a tissue
experimental absence of MMP-9 activity resulted in arterial stiff-
injury thus, overexpression of these enzymes has unfavorable ef-
ness [103]. Accordingly, in healthy individuals circulating MMP-2
fects [93]. The proteolytic activity of MMPs may be regulated at
and MMP-9 have been inversely associated with arterial stiffness
Pathophysiology of Stable Angina Pectoris Current Pharmaceutical Design, 2013, Vol. 19, No. 9 1597

Reduced Increased
oxygen supply oxygen demand

Coronary atherosclerosis- Increased wall tension

thrombosis ¾Left ventricular hypertrophy
¾Gradual occlusion ¾Hypertension
¾Sudden occlusion
Decreased coronary flow Increased heart rate
¾Vasospasm
¾Endothelial dysfunction
¾Microvascular dysfunction Exercise
¾Remodeling

Cold Stressful stimuli

Anaemia Smoking
Other causes Arterial stiffness
Fig. (1). Mechanisms affecting oxygen supply balance.

[104]. Several lines of evidence suggest that genetic factors could

CONCLUSION
affect the expression of MMPs in cardiovascular disease and influ-
ence arterial stiffness [105]. Particularly, it has been shown that Atherosclerosis is a chronic disease which represents in large
polymorphisms in MMPs genes have been positive associated with part, an inflammatory response in the vessels. Atheroma formation
arterial stiffness. For example, aortic PWV and serum MMP-9 lev- and in turn, atherosclerotic plaques seem to affect coronary flow,
els were significantly affected by variations of the -1562C>T poly- since flow-limiting obstructions are observed in patients with
morphism of MMP-9 gene with a significant gene-dose effect in chronic coronary syndrome. Local and systemic atherosclerotic
hypertension [106]. Accordingly, similar observations were also processes which lead to obstructive atherosclerotic artery disease,
present in a large cohort of healthy individuals [107]. such as vascular remodeling and microvascular dysfunction could
contribute to limited blood flow. Anginal chest pain is one of the
BALANCE OF OXYGEN SUPPLY most common complaints in the outpatient setting but, despite the
All things considered and having mentioned the underlying considerable advances regarding the pathophysiology of ischemic
mechanisms, it should be stresses that an increase in myocardial heart disease, the comprehension of the pathophysiology of the
oxygen demand, in the ground of limited myocardial oxygen sup- chronic coronary syndrome has not been fully elucidated. Increased
ply, is usually the mechanism of CCS Fig. (1). Oxidative phos- myocardial oxygen demand, in the ground of limited myocardial
phorylation and oxygen availability determine the production of oxygen supply, is usually the underlying mechanism of stable an-
useable energy in the form of ATP. More specifically, oxygen de- gina. The challenge for the clinician is to determine chronic stable
mand is affected mostly by heart rate, blood pressure, and myocar- angina and to use a systematic approach for testing and therapy
dial wall tension, in relation to the preload, afterload, and contractil- based on patient risk factors and characteristics.
ity [15]. These parameters include increased heart rate, systolic wall
CONFLICT OF INTEREST
stress, arterial stiffness, blood pressure (afterload) and diastolic wall
stress, end diastolic pressure and volume (preload) along with in- The authors confirm that this article content has no conflicts of
creased contractility that is required by increased physical activity interest.
and stressful stimuli. On the other hand, limitation to increases in
myocardial oxygen supply may be due to coronary vascular condi- ACKNOWLEDGEMENTS
tions, such as flow-limiting obstruction accompanied by inadequate Declared none.
collateral circulation. The obstruction usually is attributed to altered
smooth muscle reactivity and/or permanent factors such as ABBREVIATIONS
atheroma and thrombus. Thus, the size of the vessel lumen avail- CAD = Coronary artery disease
able for blood flow, determined by the process of vascular remodel- ED = Endothelial dysfunction
ing, seems to be of critical importance. Furthermore, given that the
level of hemoglobin defines myocardial oxygen delivery, anemia IHD = Ischemic heart disease
should worsen the consequences of an imbalance of oxygen supply CCS = Chronic coronary syndrome
[11]. Other alterations, such as hypercoagulable states may result in CBF = Coronary blood flow
increased viscosity which could contribute to limit coronary flow in
ACS = Acute coronary syndrome
CCS [108].
UA = Unstable angina
1598 Current Pharmaceutical Design, 2013, Vol. 19, No. 9 Tousoulis et al.

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Received: August 31, 2012 Accepted: September 17, 2012