PART II - ASSESSMENT OF CORONARY VASOREACTIVITY AND THE MICROCIRCULATION
TABLE OF CONTENTS
BOOKSHOP
Updated on November 16, 2019
PART II

Assessment of coronary vasoreactivity and the microcirculation

Thomas F Lüscher1, 2, Andreas F. Flammer3, Amir Lerman4, Michel T. Corban4
1. Royal Brompton & Harefield Hospital and National Heart and Lung Institute Imperial College, London, United Kingdom
2. Center for Molecualr Cardiology, University of Zurich, Zurich, Switzerland
3. Department of Cardiology, University Hospital, Zurich, USZ, Zurich, Switzerland
4. Department of Cardiovascular Disease, Mayo Clinic College of Medicine and Science, Rochester, USA

Summary

Coronary vasoreactivity, both in large epicardial arteries and in the microcirculation, is crucial to adapt blood flow to the requirements of the myocardium. The coronary circulation is regulated by endothelium-derived vasoactive substances as well as circulating hormones and autocoids and the sympathetic nervous system. The endothelium is in a strategic anatomical position between the circulating blood and vascular smooth muscle cells and hence a target of both circulating hormones and autocoids as well as cardiovascular risk factors. The latter cause endothelial dysfunction both in large coronary arteries and in the microcirculation. This is mainly due to an inactivation of the L-arginine-NO pathway and the production of reactive oxygen species, and in turn adhesion molecules, cytokines and chemokines. Endothelial dysfunction can be assessed with various invasive and non-invasive methods allowing for diagnostic studies as well as monitoring the effects of various cardiovascular drugs. Endothelial dysfunction is an early step in the atherosclerotic process preceding structural vascular changes, but predictive of the development of plaques and plaque rupture and in turn clinical events.

Introduction

Since the introduction of coronary angiography by Mason Sones in the 50ties and percutaneous peripheral and later coronary angioplasty by Andreas Grüntzig in the 70ties, these diagnostic and interventional techniques have experienced a remarkable success in clinical cardiology. However, angiography alone represents only a silhouette of the contrast agent and hence of the lumen and does not provide any information about structural characteristics of the vessel wall nor about vascular function.

In recent years several techniques to assess the functionality of the coronary arteries have been introduced both at the experimental as well as clinical level. Coronary vascular function is mainly dependent on the functional integrity of the endothelium. Endothelial dysfunction is considered an early step in the atherosclerotic process and can be regarded as the common target of cardiovascular risk factors. The aim of this chapter is (1) to provide the interventional cardiologist with essential information about the physiology of the coronary vascular bed, (2) to describe the possibilities to assess epicardial and microvascular dysfunction in humans, (3) to summarize the current knowledge in epicardial and microvascular dysfunction and (4) to propose a classification of microvascular dysfunction.

Endothelim-derived vasoactive substances

In the heart, the coronary circulation is indispensable for supplying and regulating blood flow in order to match oxygen demand and supply to the myocardium. The coronary vascular endothelium represents the inner layer of the vessel wall of both the large conduit vessels as well as the microcirculation. As a continuous and smooth monolayer of cells, the endothelium provides a non-thrombogenic surface with highly selective permeability properties. As such it regulates the exchange of molecules, among them lipoproteins between the circulating blood and the myocardium in response to environmental and molecular signals [1]. The endothelium is constantly exposed to variable degrees of shear stress leading to a flow mediated physiological adaption of healthy arteries. However, slow as well as strong and disturbed flow might alter shear stress responses thus mediating the development of atherosclerosis, plaque initiation and progression [2, 3]. The endothelium responds to shear stress by the release of a variety of endothelium-derived vasoactive substances, surface proteins and autacoids. Indeed, for adequate function a large number of substances are released in response to shear stress and blood-derived mediators, among them the vasorelaxing radical nitric oxide (NO), prostanoids and peptides such as angiotensin II and endothelin-1 ( Figure 1) [4]. NO is a highly diffusible small molecule synthesized by a family of NO synthases (NOS) from L-arginine that activates guanylyl cyclase leading to the formation of cGMP which in turn reduces intracellular Ca2+ levels. Beside its vasodilatator properties, NO also inhibits platelet adhesion and aggregation as well as other key event of the atherosclerosis process such as smooth muscle cell migration and proliferation, leukocyte adhesion and migration.

In large conduit arteries, endothelial cells release NO mainly in response to shear stress, but also to autocoids like acetylcholine, bradykinin, histamine, vasopressin, thrombin as well as serotonin and ADP (and hence platelets) [5, 6, 7, 8, 9, 10, 11, 12, 13]. Depending on the vascular bed, other endothelium-derived relaxing factors than NO seems to play a role, most importantly prostacyclin (PGI2) and the so-called endothelial-derived hyperpolarization factors (EDHF) [11, 14, 15, 16]. PGI2 is synthesized by cyclooxygenase-1 (COX-1) from arachidonic acid and increases cAMP in smooth muscle cells and platelets. In contrast to NO, the contribution of PGI2 to the maintenance of basal vascular tone of large coronary conduit arteries is minor [7]. However, PGI2 facilitates the release of NO from endothelial cells and vice versa. Furthermore, NO and PGI2 potentiate each others action in smooth muscle cells and platelets. In the presence of a reduced NO bioavailability, endothelial-derived hyperpolarization factors (EDHFs) represent a compensatory mechanism for endothelium-dependent vasodilatation [17]. Furthermore, EDHFs contribute mainly to the regulation of the coronary microcirculation and less so to that of large epicardial coronary arteries [18, 19] As a counterpart to the relaxing factors, endothelium-derived constricting factors (EDCF) take part in coronary vasomotion. Among them, endothelin-1 (ET-1) represents the most potent molecule, which leads to profound and long-lasting contractions and potentiates the effects of other vasoconstrictor hormones, particularly serotonin [20]. The production and release of ET-1 production is regulated by shear-stress, angiotensin II, thrombin, adrenaline, oxidized low-density lipoproteins and inflammatory cytokines [21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33] . Finally, endothelial cells produce prostaglandins with vasoconstrictor properties (such as PGH2 and TXA2) and reactive oxygen species that inactivate NO and may directly affect coronary vascular tone.

Interestingly, atherosclerosis develops in distinct regions of the vasculature, a fact that is partly attributed to vascular geometry and blood flow induced shear stress [3]. Flow pulsation or flow irregularities due to flow gradients, as for example in bifurcations and curvatures, makes the endothelium more susceptible to damage [34] and local low flow might alter endothelium morphological and functional (reduction of NO and PGI2, for example) characteristics thus possibly inducing early lesions [2, 35, 36]. As endothelial dysfunction and atherosclerosis develops, the role of vasoconstrictor factors becomes more dominant leading to a growing imbalance in favor of mediators leading to vasoconstriction, proliferation and inflammation. As a consequence, circulating blood cells such as monocytes, lymphocytes and platelets interact and adhere to the vessel wall and migrate into the intima leading to plaque and eventually thrombus formation ( Figure 2).

FOCUS BOX 1Endothelium-derived vasoactive substances
  • Endothelium-derived vasoactive substances play a key role in regulating vascular tone and function in response to a variety of agonists as well as shear stress
  • Nitric oxide is the main vasodilating and endothelin the main vasoconstricting substance

Coronary endothelial function

Endothelial dysfunction refers to any form of abnormal activity of the endothelium and can thus be considered as a syndrome that exhibits systemic manifestations associated with significant morbidity and mortality [37]. One of the most important contributors to endothelial dysfunction is an impaired NO bioavailability due to either an increased breakdown of it by reactive oxygen species (ROS) and – at later stages of the disease process - a decreased production of NO due to a reduced expression of eNOS [38, 39]. Indeed, most cardiovascular conditions are characterized by an overproduction of ROS and in turn increased oxidative stress [40]. ROS rapidly interact with NO to form peroxynitrate (ONNO-) and in turn reduce its bioavailability, nitrosylate vital proteins such as superoxide dismutase and prostaglandin synthase among others and directly damage cellular structures and DNA. In addition, other factors contribute to endothelial dysfunction such as chronic increase in shear stress, pressure and pulsatility as well as genetic predispositions and other so far unknown factors. As endothelial cells are a final common target of hypertension, dyslipidemia and/or diabetes, endothelial function represents an integrated index of both the overall cardiovascular risk burden and vasculoprotective factors in a given individual [41].

Interestingly, compared to other vascular beds, coronary arteries show lower endothelial NO synthase activity particularly in the microcirculation, but a higher endothelin expression [42]. This is likely related to the fact that NO regulates endothelin production [22]. The coronary vascular effects of endothelin are determined by the balance of (vasoconstrictor) ETA and (vasodilator via NO and prostacyclin) ETB- receptor activation. In healthy coronary arteries endothelin-1 maintains normal blood vessel tone, while in atherosclerotic vessels it promotes vasoconstriction as well as cellular proliferation, and angiogenesis [43]. Importantly, endothelin plasma and tissue levels are elevated in patients with coronary artery disease, atherosclerosis [44] and in particular in patients with ST-segment elevation myocardial infarction and Takotsubo syndrome [45]

FOCUS BOX 2

Any imbalance between vasodilatating and vasoconstricting factors lead to endothelial dysfunction, a condition with systemic implications and associated with morbidity and mortality. In atherosclerotic coronary arteries endothelin is the most important contributor to endothelial dysfunction and promotes vasoconstriction, cellular proliferation and angiogenesis.

Coranary microcirculation

Blood flow to the different parts of the heart is constantly adapted to different needs and changing physical and hemodynamic conditions. This adaption is primarily achieved by changes in vascular resistance within the microcirculation to match blood flow with myocardial oxygen consumption. The adaption in the heart is special because decreased oxygen supply is mainly dependent on coronary blood flow because myocardial oxygen extraction is near maximal at rest. Hence, any increase in demand can only be achieved by increasing flow. Another characteristic is the fact that due to the high intraventricular pressure during systole, coronary flow occurs primarily during diastole.

In contrast to the epicardial vessels, which do not contribute greatly to vascular resistance in the absence of significant coronary artery disease, the microcirculation is the major determinant for vascular resistance (to a lesser extent also extravascular myocardial resistance and rheologic components), thus the duration of diastole may contribute to coronary blood flow.

Distal to the large conduit coronary arteries, the arterial system is composed of pre-arterioles and precapillary arterioles ( Figure 3). The pre-arterioles maintain pressure at the origin of arterioles constant within a narrow range, even when coronary perfusion pressure or flow changes. Thus, pre-arterioles are the principal regulators of coronary blood flow. These vessels (similar to the conduit arteries) are both regulated by endothelium-dependent vasoactive substances released in response to shear stress and also the sympathetic nervous system via a-receptors (mainly in smaller coronary arteries) and b-receptors (mainly in large conduit arteries). In contrast, intramural arterioles match myocardial blood supply and oxygen consumption via local metabolic mediators such as adenosine among others [46].

Inhealthy individuals, the coronary vasculature increases resting blood flow during exercise, mental stress or other stimuli to a maximum level to match myocardial oxygen demand. This maximal increase is referred to as coronary flow reserve (CFR) and represents the ability of the vasculature to respond with an increase in coronary flow after maximal coronary vasodilatation as compared to basal coronary perfusion. In healthy adults without coronary artery disease, CFR increases more then 3-fold under these conditions. Due to autoregulation basal flow is kept constant even with changing coronary perfusion pressure. It is essential to remember, though, that large conduit arteries contribute only about 10% to the total coronary vascular resistance, unless severely stenotic, whereas the microcirculation is responsible for more than 70% ( Figure 3). However, in the presence of significant epicardial coronary artery stenoses resistance increases either during conditions of high oxygen demand or even at rest. Similarly, microvascular dysfunction due to several potential mechanisms might decrease basal coronary blood flow and/or CFR in the absence of epicardial stenosis.

Because selective coronary angiography provides direct insights into the degree of coronary artery narrowing until recently most of the research has focused on the role of epicardial coronary arteries. Indeed, percutaneous coronary revascularization strategies are very effective in relieving patients from symptoms of obstructive coronary artery disease. However, despite adequate revascularization, many patients still experience angina even if state-of-the-art therapies have been used [47]. Therefore, not only the large conduit coronary arteries, but also (or mainly) the subsequent microcirculation are likely to play a major role in the pathophysiology of ischemia and its clinical consequences.

FOCUS BOX 3

The coronary microcirculation is essential for adapting vascular resistance and thus guiding blood flow to the different parts of the heart, according to its needs. In fact, contrary to the epicardial vessels, microcirculatory vessels are the main contributors to vascular resistance, especially the pre-arterioles. The maximal increase in coronary blood flow to stimuli such as exercise, mental stress or pharmacologic agonists is referred to as coronary flow reserve.

Techniques to assess epicardial artery vasoreactivity

Several techniques to assess endothelial function have been developed. The first demonstration of endothelial dysfunction in atherosclerotic coronary arteries using intracoronary infusion of acetylcholine and quantitative coronary angiography has been published in 1986 [48]. Later, other techniques which are less invasive have been developed mainly using the forearm circulation as a surrogate for coronary arteries [49]. All techniques have their advantages and disadvantages and most importantly different vascular beds are examined. The basic principle, however, is simple: Large conduit arteries such as the coronary or brachial artery dilate in response to reactive hyperemia (flow-mediated vasodilatation) or upon intraarterial infusion of endothelium-dependent vasodilators such as acetylcholine (Ach), bradykinin or serotonin in the presence of a functionally intact endothelium, capable to release NO or other endothelium-derived vasoactive substances.

In the catheterization laboratory, vascular changes of the epicardial coronary arteries can be assessed by quantitative angiography (QCA) using ECG-gated end-diastolic frames. Many techniques and computer algorithms are available to measure coronary artery diameter or cross-sectional areas (most of them are designed to assess stenotic, rather than non-stenotic arteries). The images are analyzed either on-line during the coronary angiogram or off-line after acquiring the images, which are then stored in special image processing systems. The most critical part is to accurately detect the arterial wall of interest, which can be performed either manually, automated and semiautomated, and complex computer analysis with edge-to-edge recognition are applied. The main advantage of the computer based algorithms is their minimal observer variability [50]. Furthermore, it is crucial to calibrate against a reference dimension to get useful quantitative information (converting measured pixels into in vivo millimeters), which is normally done by measuring a contrast filled catheter with known diameter. Therefore, in order to acquire images which can be evaluated with the utmost accuracy, the segment measured should have a certain length, be at an angiographically normal site and major branching points should be spared out as this might impair the accuracy of the computer edge-detection system. Ideally, the point of interest should be acquired in biplane fashion with stable position of the image intensifier and the catheterization laboratory table. During the exposure, it is essential to get high quality images, which also implies good quality injections and a visible tip of the catheter for calibration purposes.

Transducer position and the equipment influence the accuracy of intravascular ultrasound thus emphasizing the role of selecting longitudinal image and calibrating the system for quantitative measurements [51]. The methodology to assess quantitative coronary diameters has been validated by documentation of accuracy and reproducibility ex-vivo [52, 53], and in-vivo [50, 54, 55]. Serial assessment of changes in lumen diameter yield a threshold for angiographically detectability of about 0.40mm [50, 55].

INTRACORONARY INFUSION OF VASOACTIVE SUBSTANCES

There are many physiologic vascular active agonists involved in vasomotion (see above) but some vasoactive substances can be delivered intraluminally and vascular response can be measured accordingly. Commonly, the changes in coronary artery diameter from baseline in response to intracoronary infusion of a single of multiple dosages of acetylcholine (ACh) (or other vasoactive substances, see Table 1) to measure endothelial-dependent and nitroglycerin to measure endothelial-independent vasodilation, respectively are assessed ( Figure 4). Under these conditions, coronary arteries with an intact endothelium will respond to intracoronary acetylcholine infusion with an increase in diameter (and microvascular dilatation resulting in an increase of coronary blood flow, see below). However, if the endothelial layer is dysfunctional or even disrupted, Ach produces a more or less profound vasoconstriction due to a direct activation of muscarinic receptors on smooth muscle cells, and a decrease in coronary blood flow, respectively [48]. Similarly, exercise or distal infusion of papaverine will increase shear stress on the coronary circulation and in turn elicit an increase in coronary diameter and blood flow respectively. The vasodilation to increased shear stress and acetylcholine has been shown to be prevented by infusion of an inhibitor of endothelial NO synthase such as L-NG-monomathly arginine [56].

COLD PRESSOR TEST

Besides pharmacological interventions also physiological interventions can be used to assess epicardial coronary vasoreactivity such exercise [57], pacing induced tachycardia as a surrogate for exercise [58], or cold pressor test. With the cold pressor test (CPT) subjects put their hand into ice water leading to sympathetic activation driven through the sensation of pain. This acute activation of the sympathetic system leads to the release of noradrenalin and adrenalin from nerve endings and adrenal glands [59]. The stimulation of endothelial 2-adrenergic receptors, mainly in resistance arteries [19] leads to the release of NO and endothelium-derived hyperpolarizing factors (EDHFs) leading to vasodilatation [19]. However, in the diseased arteries, namely if the endothelial cells are dysfunctional, a1-adrenergic mediated constriction of smooth muscle cells will dominate and cause vasoconstriction [60]. Of note, the dilation of normal and the constriction of atherosclerotic coronary arteries with cold pressor testing mirror the response to the endothelium-dependent dilator acetylcholine [61].

FOCUS BOX 4

Epicardial vascular function can be assessed by intracoronary infusion of vasoactive substances such as acetylcholine or nitroglycerin as well as by physiological interventions such as exercise or the cold pressor test. Changes in coronary artery diameter or area are assessed by quantitative coronary angiography.

Techniques to assess the microcirculation

Due to the fact that the microvessels are very small, imaging techniques cannot display them directly. Theoretically endomyocardial biopsies would be helpful to detect structural alterations, but performing biopsies is not practicable in a big cohort of patients as it is invasive and portrays potential risk. Furthermore, the biopsy might not represent the vessels at risk.

However, a functional assessment of the microcirculation is feasible by the assumption that the microvasculature is the major determinant of the regulation of coronary blood flow at rest and during increased demand (in the presence of maximally dilated epicardial coronary arteries). Therefore myocardial blood flow can be used as a surrogate parameter of microvascular function [47] and several techniques have been evaluated in this context. However, it is important to keep in mind, that measurements provide only an indirect assessment of microvascular function. Furthermore, in patients with obstructive coronary artery disease, caution should be used due to an heterogenous distribution of blood flow within the myocardium. At this point we will focus on methods which can be performed in a catheterization laboratory.

ANGIOGRAPHIC FRAME COUNT (TIMI)

This technique measures the number of cineangiographic frames that it takes to fill the vessel with contrast medium. The corrected TIMI (Thrombolysis in Myocardial Infarction) frame count (CTFC) provides a semiquantitative assessment of epicardial coronary blood flow. The assumption behind this index is that slow flow in the absence of significant epicardial stenosis reflects impaired of myocardial microcirculation perfusion [62]. Although CTFC has been used to measure microvascular function it has not been validated to justify its use as a research tool.

INTRACORONARY OR CORONARY SINUS THERMODILUTION

With this technique a global or regional measurement of coronary flow can be made similar to the measurement of cardiac output whit the Swan Ganz catheter. To assess the overall coronary blood flow, the coronary sinus must be catheterized selectively, because coronary sinus blood flow is mainly provided from the left ventricular myocardium. The thermodilution technique is based on the general indicator dilution theory [63]. In principle, with the injection of a bolus of saline of a known volume and temperature, the temperature curve registered distal to the injection site allows for the measurement of absolute volumetric flow. One has, however, to take into account that this method does not correct for the mass of drained myocardium, thus flow will increase with higher LV mass [64]. A further limitation is that the position of the catheter in the coronary sinus may be technically challenging in some cases.

INTRACORONARY DOPPLER MEASUREMENTS

Currently, state-of-the-art measurements of intracoronary flow involve the use of intracoronary Doppler catheters. Heparin is given several minutes before measurements. In principle, intracoronary flow velocities are measured with a steerable angioplasty guidewire with an ultrasound transducer at its tip ( Figure 4). The guidewire position should be in an area of laminar flow and to optimize the velocity signal, guidewire position must be adjusted to interrogate the maximal velocity which is located in the middle of the blood stream. Thereby, Doppler flow-velocity spectra are obtained and analyzed to determine the time-averaged peak velocity. Volumetric CBF can then be determined from the following equation: CBF = cross-sectional area x average peak velocity x 0.5 (coronary artery diameter is measured 5mm distal to the tip of the wire). With this method Coronary Flow Reserve (CFR) can be measured, an important marker of inadequate coronary blood flow response ( Figure 6). CFR is calculated as the ratio of maximal blood flow during maximal coronary hyperemia with provocative stimuli ( Table 1) divided by the resting flow. It is essential to achieve maximal hyperemia to receive physiological measurements. Adenosine induces vasodilation through direct effect on receptors located on the smooth muscle cells. This non-endothelium dependent increase in blood flow, however, induces shear stress on the coronary arteries to possible further dilate the artery. If dipyridamole is used, the cellular reuptake of adenosine into endothelial cells is inhibited, thus leading to increased extracellular adenosine concentration. Adenosine application, both intracoronary and intravenous, is generally safe but some patients may experience chest pain or dyspnea, symptoms which do not reflect ischemia, however. Because in patients with severe obstructive pulmonary disease bronchospasms have been reported, Adenosine is contraindicated in asthma. As an alternative to adenosine, intracoronary papaverine may be used in patients with normal coronary arteries and a similar, but longer lasting effect can be observed. QT-prolongation and rarely ventricular fibrillation can be rarely observed. Using this technique, a CFR below 2.5 is considered abnormal, consistent with endothelium-independent microvascular dysfunction [65].

Endothelium-dependent CFR can be calculated as percent change in CBF in response to acetylcholine and endothelium-independent CFR ratio by dividing the average peak velocity after adenosine injection by the baseline average peak velocity ( Figure 7). Coronary vascular resistance can be roughly estimated as mean arterial blood pressure divided by CBF.

One of the advantages of this Doppler measurement is its high spatial and regional resolution which allows the assessment of rapid changes. A further advantage is the possibility to measure the coronary vasoreactability at the level of the conduit (see above) as well as the resistance arteries at the same time. On the other hand, Doppler catheters do not measure blood flow, but rather velocity at the site of their position within the blood stream (which furthermore may change during hyperemia as does the velocity profile within the artery) and thus provide only an approximate value of true integrated flow [66]. The safety of Doppler flow guided measurement of microvascular function is generally very high. In our institutions no severe complications after more than 1700 cases have been noted. Moreover, Qian et al reported only rare complications (coronary spasm in 2% and ventricular fibrillation in 0.2%) [67] while Wei et al reported <1% risk of major adverse complications during invasive coronary reactivity testing [68].

As outlined earlier, several potential pitfalls and confounding condition can complicate or produce wrong measurements [69]: technical problems (guiding catheter obstruction to flow, poor calibration, signal loss) and inadequate delivery of vasoactive substances can lead to insufficient hyperemia and hemodynamic artifacts.

GUIDEWIRE-BASED PRESSURE-TEMPERATURE MEASUREMENTS

Because of the obvious difficulties to obtain high quality Doppler signals due to changes in hemodynamic conditions [70] as well as the assumption on vessel geometry and flow patterns flow assessment by Doppler has some disadvantages. Pijls and colleagues demonstrated the possibility to measure simultaneously distal coronary pressure and temperature (using indicator dilution technique, see above) using only one guide wire [71]. The product of the distal perfusion pressure and the mean transit time of an injectate at maximum hyperemia reflects microvascular resistance and was named by Fearon as the index of myocardial resistance (IMR) [72]. IMR reliably reflects myocardial resistance and is independent of the severity of epicardial stenosis [73, 74, 75]. However, this measurement overestimates microvascular function in the presence of coronary stenosis and in this situation collateral flow must be incorporated [74]. This technique is especially valuable to separately assess epicardial stenosis and microvascular resistance.

POSITRON EMISSION TOMOGRAPHY

Other functional tests to evaluate the coronary microcirculation make use of the detection of the presence of myocardial ischemia or the distribution of myocardial perfusion at baseline and/or after pharmacological stimulation (using adenosine or dipyridamole) or exercise. In the past positron emission tomography (PET) using labelled NH3 or H2O have been used as diagnostic and prognostic tools to detect flow-limiting epicardial coronary artery disease by documenting stress-induced myocardial perfusion defects. However, PET has more to offer, as it is able to quantify hyperemic myocardial blood flow or myocardial flow reserve thus identifying even early functional abnormalities of the coronary microcirculation [76]. In patients with normal perfusion after stress/rest myocardial perfusion PET, a coronary epicardial lesion is unlikely. In these patients myocardial blood flow quantification can be made by assessing myocardial flow reserve measurements. Using this technique, a CFR below 2 is considered abnormal, and 2.0-2.5 is considered borderline [76].

Other than the PET technique, cardiovascular magnetic resonance imaging using gadolinium contrast infusion, as well as contrast-enhanced echocardiography should be mentioned, but will not be discussed in more detail in this book chapter as they have been used in this context.

European Society of Cardiology (ESC) Recommendations for Assessment of Suspected Microvascular Angina

According to the 2019 ESC guidelines for the Diagnosis and Management of Chronic Coronary Syndromes, guidewire-based CFR and/or microvascular resistance (such as IMR) measurements (Class IIa recommendation) or noninvasive transthoracic Doppler of the LAD, cardiac magnetic resonance imaging (CMR) or PET (Class IIb recommendation) should be considered for evaluation of endothelial-independent microvascular dysfunction in patients with persistent angina and angiographically normal coronary arteries or non-obstructive CAD [normal instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR)]. In addition, intracoronary acetylcholine infusion with ECG monitoring should be considered in this patient population for evaluation of endothelial-dependent microvascular dysfunction (Class IIb recommendation) [77].

FOCUS BOX 5

Microcirculation cannot be displayed directly, but functional assessment is possible by the assumption that it is the main determinant of the regulation of coronary blood flow. Techniques in the catheterizations laboratory (angiographic frame counts, intracoronary or coronary sinus thermodilution, and intracoronary Doppler measurements), as well as other functional tests (Transthoracic echocardiography Doppler, Positron Emission Tomography or CMR) are used clinically to quantify blood flow changes.

Surrogate measures of coronary endothelial dysfunction

The described techniques to measure both, coronary epicardial vascular function and the assessment of the coronary microcirculation, are mainly invasive and in most cases used as a supplementary examination to coronary angiography. Therefore, non- or less invasive surrogate techniques are very popular. Although they obviously do not measure coronary vascular function directly, they have been shown to correlate with its invasive counterparts (see below). Similar to the tests performed invasively, these tests are invaluable research tools to assess vascular (patho)physiology and pharmacology (e.g. to assess vascular effect of novel therapeutic agents in their clinical development) and to complement risk factor assessment [78]

FLOW-MEDIATED VASODILATION OF BRACHIAL ARTERY

Due to its non-invasive properties flow-mediated vasodilatation of the forearm arteries (FMD) has become the most important modality to measure endothelial dysfunction. As described above, the technique measures the ability of the arteries to respond with endothelial NO release in response to reactive hyperemia after a 5-minute occlusion of the brachial artery with a blood pressure cuff. Celermajer and his colleagues were the first to measure this response in vivo, and developed this elegant technique assessing FMD of the brachial or radial artery by ultrasound technology [79] ( Figure 5). We then demonstrated that this response was indeed NO dependent as it is converted into a vasoconstriction in the presence of L-Nmonomethylarginine (L-NMMA) [7, 8]. Importantly, peripheral endothelial function as assessed by FMD correlates with coronary artery endothelial function [49]. However, although the principle of this technique is simple, it is technically challenging and therefore requires extensive training and standardization. Several attempts have been made to standardize the different protocols [80, 81].

PLETHYSMOGRAPHY OF THE FOREARM CIRCULATION

With this technique changes in forearm blood flow are measured by plethysmography in both arms after infusing vasoactive substances into a cannulated brachial artery. The main advantage of the so-called venous plethysmography is that vasoactive molecules, hormones or drugs (for instance acetylcholine or nitroglycerin) can be infused dose-dependently, thus quantifying endothelial-dependent and endothelial-independent vasodilation, respectively. The dosages required are very low and systemically not effective allowing the contralateral limb to serve as an internal control. The results are expressed as the ratio of the changes in flow measured in both arms. The response to acetylcholine is markedly reduced by intraarterial infusion of L-NMMA (but not by acetylsalicylic acid excluding PGI2 as the mediator), while that to sodium nitroprusside is enhanced demonstrating the NO is involved.

With this technique not only the conduit arteries, but rather the microcirculation of the forearm, which is not a main target organ for atherosclerosis, is investigated. However, the response to Ach is nevertheless independently predictive for future cardiovascular event [81].

FINGER PLETHYSMOGRAPHY

All accepted methods for measuring endothelial dysfunction so far are either invasive or suffer from high inter-, as well as, intraobserver variability. An emerging and promising technique is finger plethysmography (EndoPAT, Itamar MedicalR), a device which detects pulsatile arterial volume changes observer independently [81, 82, 83]. In principle, an increase in arterial blood volume in the finger tip causes an increase in pulsatile arterial column changes thus increasing the measured signal and vice versa. Similar to the assessment of endothelial function with the FMD technique, a pressure cuff is placed on one upper arm and after obtaining baseline blood volume changes, the blood pressure cuff is inflated above systolic pressure and deflated after 5 minutes to induce reactive hyperemia on one arm. As with venous plethysmography technique, the contralateral arm serves as its internal control and a calculated index between the two arms can be calculated. This index is an important marker for endothelial function, however, augmentation of the pulse amplitude after reactive hyperemia is a complex response to ischemia. It reflects changes in flow, as well as in digital microvessel dilatation and is only partly dependent on nitric oxide [84]. Importantly, however, studies demonstrated that impairment in peripheral finger endothelial function measured with EndoPATR is correlated with coronary microvascular function in patients with early atherosclerosis [85] and moreover in a cross-sectional study in 1’957 patients in the Framingham cohort, digital vascular dysfunction was associated with traditional and metabolic cardiovascular risk factors [86]. Moreover, finger plethysmography predicts cardiovascular events [87].

RETINAL VESSELS

Retinal vessels, arterioles and venules alike, are directly visualized via fundus examination, an advantage within the techniques described and suggested as a “window to the heart” [88]. While static retinal analysis (arteriovenous ratio) has been shown to be an independent predictor of cardiovascular mortality [89, 90, 91], recent research focused on dynamic retinal vessel analysis (DVA) to study vascular function via flicker-light induced vasodilatation [92].

With this method, the retina analyzed via a charge-coupled camera to determine baseline diameters and after optoelectric flicker-light stimulation alternating with 80 seconds of constant illumination phases. Shear stress induces functional hyperemia via neurovascular coupling. Oxygen demand in response to flicker-light leads to release of vasodilatory substances, particularly nitric oxide, thereby relaxing the smallest arteriolar walls. Increased blood flow then increases shear stress in bigger arteriolar segments. Intact retinal endothelium responds to shear stress with vasodilation [93, 94].

Importantly, DVA has been shown to be associated with traditional risk factors [95], is impaired in heart failure [96] and ischemic heart failure [97].

FOCUS BOX 6

Less invasive techniques to assess endothelial dysfunction have been developed. The most important are the measurement of brachial artery flow-mediated vasodilation by ultrasound, the measurement of changes in the forearm blood flow by plethysmography, as well as the assessment of pulsatile arterial volume changes with finger plethysmography (EndoPAT) and the dynamic assessment of the retinal vessels (DVA).

Clinical relevance of epicardial coronary dysfunction

Measurement of endothelial function in the epicardial coronary artery or in surrogate circulations such as the brachial or radial artery provides important clinical and prognostic information ( Figure 8). Epicardial coronary dysfunction has been documented using acetylcholine infusion [48, 98], cold pressure test and/or exercise [57] in almost every condition associated with atherosclerosis and cardiovascular disease including transplantation vasculopathy [99, 100, 101, 102].

As outlined above, there is a complex interplay between epicardial coronary arteries and disease which can be illustrated with hypertension. Indeed, this condition plays both a role in the genesis of atherosclerosis and the evolution of unstable atherosclerotic plaques [103]. Endothelial dysfunction is considered to be the key initiator in the development of atherosclerosis and characterized by impaired vasodilatation, favouring vasoconstriction as well as a procoagulant environment and increased leukocyte adhesion and transmigration.

Increased shear stress and wall stress then leads to the production of ROS [104], growth factors such as angiotensin II and other neurohumoral factors all further contributing to endothelial dysfunction [105]. Thus, endothelial dysfunction is a potential initiating event of vascular injury as well as local inflammation. Of note, such functional alterations are followed by structural vascular changes [106].

Interestingly, although atherosclerosis conceptually is a diffuse and systemic disease testing of endothelial function of epicardial coronary arteries often reveals segmental dysfunction [107]. Segmental endothelial dysfunction is also observed during the progression of atherosclerosis as well as in complications of the disease process, specifically plaque rupture [108]. Indeed, those segments in which endothelial dysfunction is most pronounced are the ones where vulnerable plaques typically develop and plaque rupture or erosion might occur. Furthermore, segments with endothelial dysfunction in patients with minimal atherosclerosis are associated with plaques containing a necrotic core, a hallmark of plaque rupture [109]. Importantly, the development of endothelial dysfunction at the level of the epicardial vessels facilitates thrombus formation as NO is a potent platelet inhibitor via the intracellular formation of cyclic GMP.

Recently it has been suggested that coronary artery segments that exhibit vasoconstriction in response to acetylcholine have specific features of vulnerable plaques [109]. However, it remains unclear which mechanisms are responsible for the fact that only certain but not all coronary segments are affected, but endothelial function may be a potential mediator.

A special form of epicardial coronary dysfunction is coronary artery vasospasm, which was first described by Prinzmetal in 1959 [110]. In this syndrome an increased response to a variety of vasoconstrictor agents such as ergonovine, serotonin, but also acetylcholine is characteristic. The mechanisms have not been fully elucidated, but an increased autonomic tone, increased responsiveness of vascular smooth muscle cells as well as endothelial dysfunction due to a decreased NO and/or increased endothelin release might be involved. Besides ergonovine, provocative testing with acetylcholine has been used to diagnose spasm [111].

PROGNOSIS

Given its role in the atherosclerotic process, it is not surprising that many studies documented a prognostic role of endothelial function measurements in the coronary (and for that matter also the peripheral) circulation. First evidence came from patients with non-obstructive coronary artery disease. Indeed, a higher incidence in cardiovascular [108, 112] and cerebrovascular events was noted in those with impaired coronary vascular function [113]. Moreover, coronary endothelial dysfunction is able to predict an increased risk of angina hospitalization [114] and incidence of further cardiovascular events even in patients without coronary artery disease [115, 116] as well as in heart transplant recipients [117].

There is a strong association between coronary and peripheral endothelial dysfunction and cardiovascular events as illustrated by a metaanalysis involving 2’500 patients [37]. Of note, there is similar power of coronary and peripheral endothelial dysfunction to predict cardiovascular events. Interestingly, these events may also occur in remote from the sites in which endothelial dysfunction were detected underscoring the systemic nature of endothelial dysfunction [118] [113]. Indeed, a growing body of evidence demonstrates that vascular endothelial dysfunction is a systemic disease affecting multiple vascular beds, with cardiac, cerebrovascular, renal, ophthalmic, and thrombotic manifestations [119, 120, 121, 122].

FOCUS BOX 7

Epicardial endothelial dysfunction is seen in almost every condition associated with atherosclerosis and gives important prognostic information. Although atherosclerosis is a diffuse and systemic disease, epicardial vascular dysfunction is often segmental and those segments are especially vulnerable of plaque development, rupture and thrombus formation.

Clinical relevance of microvascular dysfunction

Coronary flow reserve is mainly a measurement of the ability of the microvasculature to respond to a stimulus and therefore to adapt to the requirements of the myocardium (46). However, it has to be taken into account, that some conditions might decrease CFR without microcirculatory dysfunction present. Most importantly, tachycardia, hypoxemia, anemia or myocardial hypertrophy increase basal blood flow due to increased myocardial demand, whereas obstructive coronary artery disease, increased viscosity or elevated left ventricular filling pressures decrease maximal flow. Both conditions reduce CFR without the presence of microvascular dysfunction or endothelial dysfunction necessarily present (see Figure 9).

After excluding such conditions, impaired CFR is an important marker of microvascular dysfunction, which can be classified according to Camici and Crea [46] into (A) Coronary microvascular dysfunction in the absence of obstructive CAD and myocardial diseases; (B) Coronary microvascular dysfunction in the presence of myocardial disease; (C) Coronary microvascular dysfunction in the presence of obstructive CAD and (D) Iatrogenic coronary microvascular dysfunction. However, this classification does not take into account the pathophysiological mechanisms as microvascular function can be either structurally or functionally impaired.

STRUCTURAL MICROVASCULAR DYSFUNCTION

In structural microvascular dysfunction the small vessels cannot respond to increased oxygen or blood demand, respectively, due to alterations in vascular structure or of the surrounding tissues, vascular rarefaction or luminal obstruction. These structural changes primarily restrict coronary flow reserve, while in most cases baseline flow is not affected ( Figure 9). However, in the presence of severe structural alterations or with luminal obstruction of large coronary arteries, baseline flow might also be limited. Such conditions perhaps can be best compared to restrictive lung diseases, were breathing and maximal oxygen intake is limited by structural changes in the lung tissues.

Clinically, structural impairment is seen in patients with myocardial disease. In primary cardiomyopathies such as dilated or hypertrophic cardiomyopathy CFR is severely blunted [123, 124]. In the later the hypertrophied septum and to a lesser degree the hypertrophied LV free wall contribute due to extensive remodeling of intramural arterioles [125]. Importantly, impaired CFR in these patients is an important predictor for cardiovascular death [126, 127]. In patients with arterial hypertension, in addition to the commonly present functional impairment due to endothelial dysfunction, structural microvascular dysfunction due to vascular remodeling is also present, even in the absence of frank LV hypertrophy [128]. Intramural arterioles and interstitial fibrosis decrease the density of the coronary microvasculature. Similar adaptive changes due to microvascular remodeling, perivascular fibrosis, vascular rarefactions and extramural compression occur in patients with aortic stenosis, which explains the reduced CFR in these patients even in the presence of angiographically normal coronary arteries [129].

Other examples include vascular-wall infiltration due to infiltrative heart disease like Fabry disease, where glycosphingolipids are deposited in myocytes as well as in endothelial cells or amyloidosis where amyloid proteins accumulate intracellularly. In these patients CFR is usually severely impaired, thus possibly explaining the high frequency of angina in this patient population even in the presence of a normal coronary angiography [130]. Finally, luminal obstruction might occur due to microembolization in acute coronary syndromes or iatrogenic after percutaneous interventions.

FOCUS BOX 8 Structural microvascular dysfunction
  • In structural microvascular dysfunction coronary flow reserve is restricted by alterations in vascular structure or the surrounding tissues while baseline flow normally is not affected
  • This type of dysfunction is seen in patients with myocardial diseases and impaired CFR is an important predictor for cardiovascular death in these patients

FUNCTIONAL MICROVASCULAR DYSFUNCTION

Whereas structural microvascular impairment, as outlined above, mostly is a reflection of severe or advanced disease and is often irreversible, functional abnormalities occur commonly already in early stages of a disease process, long before structural changes have developed. In functional microvascular dysfunction basal CBF is mostly normal, however the vessel is not able to dilate adequately in response to an increased oxygen or blood demand ( Figure 9). This condition is almost always attributed to endothelial dysfunction. In some cases, dysfunction of the smooth muscle cells may also be present.

As in large coronary arteries, microvascular endothelium dysfunction occurs due to several reasons as outlined above in this book chapter. The most important contributors are classical cardiovascular risk factors, drugs or local factors (e.g. stents eluting sirolimus or paclitaxel). Indeed, a decreased CFR is found in smokers [131], hypertensives, in dyslipidemia and in diabetes [132, 133, 134]. Importantly, in patients with normal or minimally diseased coronary arteries, the cardiovascular event rate is 3-fold higher in patients with the lowest as compared to those in the highest tertile of CFR [135]. Therefore, the presence of microvascular dysfunction is a strong predictor of clinical outcome, even in the absence of hemodynamically significant epicardial disease [137].

Thus, the fact that abnormalities of endothelial function in the coronary microcirculation occur before structural changes are noted may allow for early identification of asymptomatic individuals with intermediate or low cardiovascular risk. This would allow implementing adequate preventive treatment strategies in early stages of the disease process. Furthermore, functional microcirculatory dysfunction provides important information in patients with obstructive coronary disease and in those patients with chest pain despite angiographically normal coronary arteries. The clinical importance of microvascular dysfunction in those important clinical conditions is highlighted below.

MICROVASCULAR DYSFUNCTION IN OBSTRUCTIVE CORONARY ARTERY DISEASE

In acute coronary syndromes, acute ST elevation myocardial infarction in particular, reopening of the (partly-)closed vessel is a mainstay of therapy. However, in up to 50% of patients even after reopening the vessel, normal myocardial reperfusion is not accomplished, which refers for the phenomenon of slow or no-reflow, an expression of microvascular dysfunction [136]. Indeed microvascular dysfunction has been documented in most studies after an acute event and is indicative of an impaired prognosis [137]. CBF is significantly reduced not only in the culprit but also in the non-culprit coronary arteries, both before and after an acute coronary intervention [138]. However, whether microcirculatory dysfunction is a mediator or a simply a consequence of the initial event is still a matter of debate. The fact that during percutaneous coronary interventions debris can be obtained by the use of distal protection devices and atherothrombotic material can be retrieved after ballooning and especially after stent implantation, argues in favor of embolic microcirculatory obstruction as a consequence of the initial event or the intervention [139]. However, experimental models of plaque rupture demonstrated a marked increase in distal vascular resistance as a consequence of severe microvascular vasoconstriction rather than distal embolization [140]. This pointed to the possibility that endothelin as well as tissue factor as important mediators of this vasoconstriction, as both molecules are highly expressed in atherosclerotic plaques and in plasma of these patients. Furthermore, microparticles as a consequence of regional dissemination of proinflammatory activity may be other contributors [141, 142, 143]. Therefore, it is currently assumed that a “vulnerable” microcirculation is a requirement rather than an innocent bystander of impaired CFR in ACS. The fact that plaque rupture can remain clinically silent in some patients and, on the other hand have devastating consequences is still puzzling. The vulnerability of the microcirculation with its preexisting dysfunction might be the missing link and therefore the integrity of the microcirculation most likely plays an integral role in the evolution of an ACS. Thus, it can be postulated that for an acute coronary event not only the presence of a vulnerable plaque is necessary, but also a vulnerable myocardium with its dysfunctional microcirculation [139].

When studying microvascular function in patients with single vessel disease, it is remarkable that microvascular function is impaired even in those myocardial territories supplied by angiographically normal coronary arteries [144]. This highlights the fact that these regions are involved in the pathophysiology of the disease or are at least also affected by the acute event. This might explain the fact that in patients with stable angina even after successful intervention of the diseased vascular segment symptoms might persist. Furthermore studies comparing the effect of state-of-the-art medical treatment with percutaneous coronary interventions in patients with stable angina showed no significant difference in prognosis [145]. The fact that impaired CFR before coronary intervention predicts post-procedural CFR and procedure-related myocardial injury is likely related to pre-existing microvascular dysfunction which renders the heart prone to injury [146, 147].

MICROVASCULAR DYSFUNCTION IN PATIENTS WITH NORMAL CORONARY ANGIOGRAMS

Many patients do not show obstructive coronary disease, but do suffer from symptoms and/or ischemia. The prevalence of non-obstructive coronary artery disease in patients undergoing clinically indicated coronary angiography for chest pain is 30-50% [148, 149]. Therefore better strategies for risk stratification are needed, as diagnostic coronary angiography is not an optimal tool to detect myocardial ischemia [149]. Indeed, over 60% of patients with signs and/or symptoms of ischemia and non-obstructive coronary artery disease have non-have coronary microvascular dysfunction [150]. Therefore, microvascular dysfunction might be the missing link and thus should be appropriately assessed.

In patients with symptoms, but without obstructive coronary disease nor with evidence of large-vessel spasm, reduced endothelium-dependent coronary vasodilation has been demonstrated [151]. Thus, these patients suffer of an abnormally decreased CFR to stimuli such as exercise and mental stress among others. The exact mechanism for the anginal pain, however, remains unclear [152]. In one study, characteristic pain was provoked in 86% of patients with microvascular angina by electric stimulation (RV pacing) at a heart rate 5 beats faster than their resting heart [153]. Moreover, pacing in these patients led to an increased concentration of the vasoconstrictor peptide endothelin-1 in the coronary sinus [154]. Other pathophysiologically linked abnormalities are insulin resistance, abnormal autonomic control, enhanced sodium/hydrogen exchange activity and microvascular spasm [155], however there is a lack of relationship to conventional risk factors [156].

Another approach in these patients is to classify them into (1) those with microvascular dysfunction secondary to certain states like inflammatory or autoimmune disease [157], which are known to increase endothelin levels and (2) in those with a primary, idiopathic microvascular dysregulation. It can be postulated that primary microvascular dysfunction represents an own entity, with inadequate (temporary) constriction or insufficient dilatation of the pre-arterioles or arterioles to different stimuli like emotional or mechanical stress.

Importantly, both, endothelial-independent and endothelial-dependent coronary microvascular dysfunction predict increased risk of major adverse cardiovascular events and increased mortality risk, especially in women with signs and symptoms of ischemia, but absence of obstructive coronary artery disease [114, 158, 159]. Furthermore, not only a high prevalence of low CFR was recently demonstrated in patients with heart failure with preserved ejection fraction (HFpEF) [160], but also a high incidence of future diastolic dysfunction and HFpEF development in patients with low baseline CFR [161]. Similarly, coronary endothelial dysfunction was independently associated with left ventricular diastolic dysfunction and heart failure with preserved ejection fraction hospitalizations in patients with non-obstructive CAD [162, 163] further re-enforcing the importance of coronary endothelial and microvascular function assessment.

FOCUS BOX 9

In functional microvascular dysfunction the vessel is not able to dilate adequately to an increased oxygen or blood demand and this is mostly attributed to endothelial dysfunction. The presence of functional microvascular dysfunction is an important predictor of clinical outcome, even when coronary arteries seem normal or minimally diseased in patients with and without chest pain.

In obstructive coronary artery disease and acute coronary syndrome, microvascular dysfunction can also be observed in the non-culprit vessel raising the question whether this is a consequence or a mediator of the initial event. Moreover, microvascular obstruction detected by CMR imaging in the non-infarct related arteries has been recently associated worse major adverse cardiovascular events in revascularized STEMI patients [164].

MICROVASCULAR dysfunction in takotsubo Syndrome

Tako Tsubo Syndrome (TTS) is an acute cardiac condition, intitially described in Japan in 1990, that typically presents very much like an ST-segment elevation myocardial infarction with chest pain, dyspnea and ECG changes [165]. At angiography, the coronary arteries, however, are normal, but left ventricular angiography reveals massive dysfunction with the classical apical ballooning appearance. Troponin levels are usually only modestly increased, while NT-brain natriuretic peptide is markedly elevated [166].

TTS primarily affects postmenopausal women and is triggered typically by psychological and physical stimuli, most commonly in patients with neurological, psychological and psychiatric disorders. [165] Although initially considered rare, it has recently been recently recognized that it is much more common occurring in up to 4% of patietns presenting as acute coronary syndromes when looked for appropriately.

TTS is not a harmless disease, but has a 4-5% acute mortality and some patients may have a second and third event. Furthermore, TTS is associated with acute heart failure, cardiogenic shock, ventricular rupture, stroke, arrhythmias and sudden death. So far, there is no specific treatment available for this condition.

The mechanisms involve a marked central activation, most likely due to structural alteration of the mid brain and the amygdala in particular, massive sympathetic outflow from the cardiovascular centers and release of noradrenalin, adrenalin and endothelin. [165] The latter mediator may explain the massive and prolonged microvascular constriction of the coronary circulation over days to weeks leading to ischemia as reflected by large apical perfusion deficits and impaired contractility. Indeed, patients with Takotsubo syndrome do have endothelial dysfunction, also outside the acute episode [167].

Therapeutic approach to coronary vessel dysfunction

In discussing treatment for coronary epicardial and microvascular dysfunction, it has to be taken into account that several potential mechanisms underlying various diseases and conditions may be involved. Especially for structural microvascular dysfunction, treatment should - if possible - be focused on the underlying etiology. For example, patients with microvascular dysfunction in the context of a cardiomyopathy improve with adequate heart failure therapy mainly to a reduction in left ventricular filling pressure [168, 169]. Any disease leading to structural microvascular dysfunction, like hypertension, infiltrative- or valvular diseases should be treated adequately. Valvular replacement or repair, respectively, also improves coronary vascular function after surgery [170, 171].

In patients with functional microvascular dysfunction, endothelial dysfunction is considered as a central therapeutic target. In theory, lifestyle factors and medications that increase the release or prevents the degradation of endothelial derived relaxing factors, NO in particular, and those which decrease production of endothelial-derived constricting factors such as endothelin among others, should improve endothelial function. Importantly, endothelial dysfunction is potentially partly reversible.

LIFESTYLE FACTORS

The most important lifestyle modification is probably smoking cessation, which clearly demonstrates a positive effect on coronary endothelial function [172]. However, microvascular dysfunction cannot be improved by smoking cessation [173]. This demonstrates the differences in epicardial endothelial function and the microvasculature and its complex, and not yet fully understood interactions between both. Other lifestyle modifications have either demonstrated to be beneficial for microvascular or epicardial coronary dysfunction by increasing NO bioavailability like physical exercise [174], weight reduction and food rich in fruit and vegetables, including cocoa [100].

BLOCKER OF THE RENIN-ANGIOTENSIN SYSTEM

In general, antihypertensive treatments, like angiotensin-converting enzyme (ACE)-inhibitors, calcium channel blockers and certain b-blockers, in particular the NO-group containing molecule nebivolol, might reverse endothelial dysfunction in hypertensive patients. Thus, in patients with hypertension, blood pressure management with these drugs is important, for both, epicardial and microvascular dysfunction. ACE-inhibitors seem to play an especially important role, as several mechanisms lead to enhanced NO release and bioactivity, including preventing the breakdown of bradykinin, a potent NO releaser and by reducing the angiotensin II induced increase in NAD(P)H oxidase activity [175]. These medications have been shown to consistently improve coronary and peripheral endothelial function [176, 177] .

STATINS

Probably the most important drugs improving endothelial and microvascular functions are the statins. These agents improve peripheral endothelial function through their anti-inflammatory and antioxidant properties, as well as due to the restoration of the vascular NO bioavailability [178]. However, in epicardial coronary arteries, two large trials were unable to demonstrate an improvement of epicardial coronary artery dysfunrction in response to acetylcholine within a 6 months period [98] [179]. Possibly, more time is required to exert a protective effect in these arteries.

Statins also play an important role in partly restoring microvascular function [180]. An impressive 74% reduction in the incidence of the no-reflow phenomenon in patients taking statins before admission of acute myocardial infarction hints towards a preservation of the microvascular integrity [181].

OTHER DRUGS

Potentially the direct administration of the NO releasing drug nitroglycerin is able to dilate large conduit coronary artery, but importantly has no impact on the coronary microcirculation and thus is unable to increase coronary blood flow [182]. This is due to the lack of enzymatic conversion of nitroglycerin to nitric oxide in the resistance-regulating arteries. Furthermore, they are not suitable for chronic treatment, mainly because of tolerance and their potentially deleterious proxidative effect due to increased vascular production of reactive oxygen species. Furthermore, they do not improve endothelial function per se. However, supplementing tetrahydrobiopterin BH4, an important cofactor of NOS has been shown to increase NO and to acutely improve endothelial dysfunction in many studies [183, 184, 185], but long term supplementation failed to have any clinical impact. L-arginine, the substrate for the endogenous NO formation leads to improved endothelial functions in hypertensive patients and might be a promising substance [186, 187].

Calcium channel blockers are able to reduce calcium entry though L-type voltage-dependent channels of the vascular muscle cells and thus are able to dilate coronary and other arteries. Furthermore, some calcium channel blockers might activate endothelial NOS or have antioxidative properties thus increasing NO bioavailability [188]. Indeed, in the ENCORE-1 and ENCORE-2 trial long acting nifedipine consistently improved coronary endothelial dysfunction in patients with stable CAD even after cessation of the drug [98, 189] .

Other promising agents for the coronary vasculature are the endothelin antagonists because coronary arteries show a higher endothelin activity as compared to other vascular beds [42]. Importantly, endothelin levels are elevated in patients with coronary endothelial dysfunction and the related risk factors, as well as in heart failure. Thus endothelin-receptor antagonists hold the potential to beneficially impact on endothelial function in these patients. At least in ApoE knockout mice fed a high fat diet, ETA-receptor blockade improves endothelial function and even reduced atherosclerotic plaque development [190]. In humans recent studies demonstrated an improvement in coronary endothelial function after intracoronary infusion of an ETA-receptor antagonists [191]. Also in the long term the coronary microcirculation function can be improved after 6 month therapy with the ETA-receptor antagonists atersatan [192].

EVALUATION OF CORONARY DEVICES

In the light of long-term safety concerns, especially with regard to stent thrombosis, both coronary epicardial endothelial function as well as coronary microvascular function measurements can help to assess safety, especially as new generations of stents are being developed and undergo clinical evaluations [193] . Al mayor components, the scaffolds (especially when bioabsorbable), the polymer and the drug might impact on endothelial function. Devices which preserve vascular biology or return to normal endothelial function shortly after implantation are presumably better than those with long-term impairment of vascular biology [194].

Importantly, testing, diagnosis and treatment of coronary endothelial and microvascular dysfunction have indeed been shown to not only improve angina symptoms but also quality of life, vitality, general and mental health [195, 196].

FOCUS BOX 10

Treatment of structural microvascular dysfunction should focus on the underling disease, and in patients with functional dysfunction, endothelial dysfunction is considered the central therapeutic target. Thus lifestyle interventions and medications which increase the release or prevent the degradation of nitric oxide should be considered.

Personal perspective - Thomas F. Lüscher

Initially, coronary artery disease was considered a structural disease mainly determined by the degree of luminal narrowing. More recently, however, it was recognised that coronary arteries are not static tubes, but rather living organs able to react to circulating blood as well as to the requirements of the body by dilating during conditions of increased need, i.e., exercise and constriction during rest. This so-called flow-mediated vasodilation is now known to be mediated by the release of nitric oxide in response to shear stress exerted by the circulating blood. In addition, it was recognised that coronary arteries can react to emotional stress as well as local hormones and autacoids by either vasodilation or vasoconstriction. This has led to a more physiological concept of coronary artery disease and the recognition that structural and functional changes go hand in hand and determine the amount of ischaemia occurring under these conditions, i.e., during cold exposure, exercise and anger, etc. Indeed, in some patients with coronary vasospasm and microvascular disease, functional alterations of the coronary arteries are more important than structural narrowing. With the development of flow and pressure wires as well as other imaging technologies, it also became possible for clinicians to visualise and quantify these functional aspects of coronary regulation. Their use in clinical practice will lead to a more sophisticated work-up of patients, a better understanding of coronary function and more individualised treatments.

Acknowledgements

The research of the investigators was supported by grants from the Swiss National Research Foundation (to TFL), the Swiss Heart Foundation (to TFL), and the National Institute of Health (NIH Grant HL92954 and AG31750 to AL). AJF was supported by the Walter and Gertrud Siegenthaler Foundation, the young academics Support Committee of the University of Zurich, and the Swiss foundation for medical-biological scholarships (SSMBS; SNSF No PASMP3_132551).

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