REVIEWS Coronary microvascular dysfunction: mechanisms and functional assessment Paolo G. Camici, Giulia d’Amati and Ornella Rimoldi Abstract | Obstructive disease of the epicardial coronary arteries was recognized as the cause of angina pectoris >2 centuries ago, and sudden thrombotic occlusion of an epicardial coronary artery has been established as the cause of acute myocardial infarction for >100 years. In the past 2 decades, dysfunction of the coronary microvasculature emerged as an additional mechanism of myocardial ischaemia that bears important prognostic implications. The coronary microvasculature (vessels 0.3) are used to destroy all microbubbles in the myocardium,
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REVIEWS Diastole Subendocardium
Pericardial space
Subepicardium LV lumen
Intramural arteries
Relaxation Plumen
Ppericardium
PIM
Pvein
Venular/ arteriolar waterfall
Venous waterfall
Ppericardium
Plumen PIM
PIM
Increased blood pressure
Epicardial artery
Diastole
Systole Contraction Plumen Elastance/ shortening
PIM Plumen PIM IM
PPIMIM
Waterfall/ IM pump
Deformation
Systole
Figure 4 | Coronary microvascular dysfunction can result from abnormal extravascular pressure. Schematic drawing of the intramyocardial vasculature and the extravascular forces acting on the vasculature during diastole and systole. The relative magnitude of extravascular forces (also known as PIM) in systole and diastole are proportional to the size of letters and arrows.7 Abbreviations: IM, intramyocardial; LV, left ventricular; PIM, intramyocardial pressure; Plumen, pressure in left ventricular cavity; Ppericardium, pressure in the pericardial space; Pvein, pressure in the vein.
after which the rate of myocardial microbubble replenishment is measured. Use of a continuous infusion of contrast reduces the attenuation artefacts arising from the high contrast intensity in the left ventricular cavity.37 Time versus acoustic intensity curves are generated from the myocardial regions of interest, and fitted to the exponential function y = A(1−e−βt), where y is the acoustic intensity at a pulsing interval t, A is the plateau acoustic intensity, and β is a constant that represents the rate of rise of acoustic intensity (that is, mean microbubble velocity).38 With this method, MBF velocity and myocardial blood volume (the value A in the equation mentioned above) can be assessed: A is normalized to the acoustic intensity value from the left ventricle cavity, which provides a measure of the myocardial blood volume fraction, and the product of myocardial blood volume fraction and MBF velocity provides an estimate of MBF.36 A modified version of this approach has been validated against PET measurements of MBF in humans.39 Reductions in MBF can reflect a decrease in myocardial blood volume alone (after infarction, when the infarct-related artery is patent), a decrease in blood velocity alone (owing to significant stenosis), or a combination of both (as is the case in infarcted myocardium subtended by collaterals or by an
artery with a very severe, flow-limiting stenosis).36 MCE has been validated against single-photon emission CT and invasive angiography in multiple laboratories.37 Although MCE is perceived as safe, the risk associated with the use of some ultrasound contrast agents should be judged carefully, because severe adverse reactions have been reported, albeit rarely.40 MCE has proven to be a useful tool for identifying patients with the no-reflow phenomenon after interventional or thrombolytic treatment for acute myocardial infarction.37,41–43 In 2012, real-time perfusion echocardiog raphy with dipyridamole was used in a large cohort of patients with known or suspected CAD to assess the prognostic value of visually assessed myocardial perfusion and wall motion analysis in the context of hard cardiac events.44 The results showed that perfusion abnormalities were independent and incremental predictors of death and nonfatal myocardial infarction. Normal perfusion was always coupled with normal wall motion response, which enabled the identification of low-risk patients who had better outcomes than patients with normal wall motion but abnormal perfusion. This study highlighted the superior sensitivity of myocardial perfusion for predicting adverse cardiac events (which, nevertheless, was less specific than wall motion).44 The vast majority of available MCE studies have focused on impairment of vasodilatation. For instance, the effects of cocaine (a powerful sympathomimetic vasoconstrictor) on the microvasculature have been compared with those of metabolic vasodilatation induced by dobutamine.45 Lowdose dobutamine increased microvascular flow velocity, but left capillary blood volume unchanged. Conversely, low (nonintoxicating) doses of cocaine reduced capillary blood volume, but had no effect on microvascular flow velocity, suggesting that these effects were mediated by a prominent constriction of the arterioles (as opposed to spasm of the large epicardial arteries, which would reduce microvascular flow velocity). These data prove the detri mental effect of nonintoxicating doses of cocaine on coronary microcirculation,45 and provide an insight into the mechanisms leading to other cardiac conditions, such as Takotsubo cardiomyopathy.46,47
Positron emission tomography PET is a well-validated technique that can provide non invasive, accurate, and reproducible quantification of regional MBF in humans.11,48 MBF measurement using PET is achieved by continuous monitoring of the radioactivity emitted by an intravenously administered tracer (Table 1), in the circulation and the myocardium. The kinetics of radiotracer uptake in the myocardium are derived from time–activity curves in the left ventricular cavity (input function) and the myocardium (Figure 5); fitting these time–activity curves with an operational equation provides accurate estimates of MBF (in ml/min g–1 of tissue). A new generation of machines for 3D PET tomography have become available. The main advantage of these scanners is their high sensitivity, which enables improved intrinsic spatial resolution and a reduced radiation dose to patients (Table 1).49,50 At present, discrimination between
NATURE REVIEWS | CARDIOLOGY
ADVANCE ONLINE PUBLICATION | 5 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Table 1 | Comparison of PET tracers used to assess myocardial blood flow Tracer
Source
Half-life
15
O-labelled water (H215O)49
On-site cyclotron
2 min
13
N-labelled ammonia (13NH3)50
On-site cyclotron
Rb (cationic K+ analogue)167 82
F-flurpiridaz168
18
Dose* (MBq)
Effective dose (mSv)
Positron track length‡ (mm)
Features
370
0.8
2.5
Metabolically inert and freely diffusible. Virtually complete myocardial extraction, independent of flow rate and myocardial metabolism.165
10 min
1,100
2.4
1.5
Myocardial extraction fraction
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www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Diastole Subendocardium
Pericardial space
Subepicardium LV lumen
Intramural arteries
Relaxation Plumen
Ppericardium
PIM
Pvein
Venular/ arteriolar waterfall
Venous waterfall
Ppericardium
Plumen PIM
PIM
Increased blood pressure
Epicardial artery
Diastole
Systole Contraction Plumen Elastance/ shortening
PIM Plumen PIM IM
PPIMIM
Waterfall/ IM pump
Deformation
Systole
Figure 4 | Coronary microvascular dysfunction can result from abnormal extravascular pressure. Schematic drawing of the intramyocardial vasculature and the extravascular forces acting on the vasculature during diastole and systole. The relative magnitude of extravascular forces (also known as PIM) in systole and diastole are proportional to the size of letters and arrows.7 Abbreviations: IM, intramyocardial; LV, left ventricular; PIM, intramyocardial pressure; Plumen, pressure in left ventricular cavity; Ppericardium, pressure in the pericardial space; Pvein, pressure in the vein.
after which the rate of myocardial microbubble replenishment is measured. Use of a continuous infusion of contrast reduces the attenuation artefacts arising from the high contrast intensity in the left ventricular cavity.37 Time versus acoustic intensity curves are generated from the myocardial regions of interest, and fitted to the exponential function y = A(1−e−βt), where y is the acoustic intensity at a pulsing interval t, A is the plateau acoustic intensity, and β is a constant that represents the rate of rise of acoustic intensity (that is, mean microbubble velocity).38 With this method, MBF velocity and myocardial blood volume (the value A in the equation mentioned above) can be assessed: A is normalized to the acoustic intensity value from the left ventricle cavity, which provides a measure of the myocardial blood volume fraction, and the product of myocardial blood volume fraction and MBF velocity provides an estimate of MBF.36 A modified version of this approach has been validated against PET measurements of MBF in humans.39 Reductions in MBF can reflect a decrease in myocardial blood volume alone (after infarction, when the infarct-related artery is patent), a decrease in blood velocity alone (owing to significant stenosis), or a combination of both (as is the case in infarcted myocardium subtended by collaterals or by an
artery with a very severe, flow-limiting stenosis).36 MCE has been validated against single-photon emission CT and invasive angiography in multiple laboratories.37 Although MCE is perceived as safe, the risk associated with the use of some ultrasound contrast agents should be judged carefully, because severe adverse reactions have been reported, albeit rarely.40 MCE has proven to be a useful tool for identifying patients with the no-reflow phenomenon after interventional or thrombolytic treatment for acute myocardial infarction.37,41–43 In 2012, real-time perfusion echocardiog raphy with dipyridamole was used in a large cohort of patients with known or suspected CAD to assess the prognostic value of visually assessed myocardial perfusion and wall motion analysis in the context of hard cardiac events.44 The results showed that perfusion abnormalities were independent and incremental predictors of death and nonfatal myocardial infarction. Normal perfusion was always coupled with normal wall motion response, which enabled the identification of low-risk patients who had better outcomes than patients with normal wall motion but abnormal perfusion. This study highlighted the superior sensitivity of myocardial perfusion for predicting adverse cardiac events (which, nevertheless, was less specific than wall motion).44 The vast majority of available MCE studies have focused on impairment of vasodilatation. For instance, the effects of cocaine (a powerful sympathomimetic vasoconstrictor) on the microvasculature have been compared with those of metabolic vasodilatation induced by dobutamine.45 Lowdose dobutamine increased microvascular flow velocity, but left capillary blood volume unchanged. Conversely, low (nonintoxicating) doses of cocaine reduced capillary blood volume, but had no effect on microvascular flow velocity, suggesting that these effects were mediated by a prominent constriction of the arterioles (as opposed to spasm of the large epicardial arteries, which would reduce microvascular flow velocity). These data prove the detri mental effect of nonintoxicating doses of cocaine on coronary microcirculation,45 and provide an insight into the mechanisms leading to other cardiac conditions, such as Takotsubo cardiomyopathy.46,47
Positron emission tomography PET is a well-validated technique that can provide non invasive, accurate, and reproducible quantification of regional MBF in humans.11,48 MBF measurement using PET is achieved by continuous monitoring of the radioactivity emitted by an intravenously administered tracer (Table 1), in the circulation and the myocardium. The kinetics of radiotracer uptake in the myocardium are derived from time–activity curves in the left ventricular cavity (input function) and the myocardium (Figure 5); fitting these time–activity curves with an operational equation provides accurate estimates of MBF (in ml/min g–1 of tissue). A new generation of machines for 3D PET tomography have become available. The main advantage of these scanners is their high sensitivity, which enables improved intrinsic spatial resolution and a reduced radiation dose to patients (Table 1).49,50 At present, discrimination between
NATURE REVIEWS | CARDIOLOGY
ADVANCE ONLINE PUBLICATION | 5 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Table 1 | Comparison of PET tracers used to assess myocardial blood flow Tracer
Source
Half-life
15
O-labelled water (H215O)49
On-site cyclotron
2 min
13
N-labelled ammonia (13NH3)50
On-site cyclotron
Rb (cationic K+ analogue)167 82
F-flurpiridaz168
18
Dose* (MBq)
Effective dose (mSv)
Positron track length‡ (mm)
Features
370
0.8
2.5
Metabolically inert and freely diffusible. Virtually complete myocardial extraction, independent of flow rate and myocardial metabolism.165
10 min
1,100
2.4
1.5
Myocardial extraction fraction
