TTDE has been used to assess CMV dilation in several clinical conditions known to be characterized by CMV dysfunction, showing results comparable to those found in the same groups of patients with other, more standardized methods. Although studies directly validating TTDE in these clinical conditions are lacking, the concordant results with studies using other methods further support the reliability of this simple noninvasive tool.
A significant reduction of CFR, in particular, has been documented with TTDE in patients with cardiovascular risk factors,38,39 those with idiopathic dilated cardiomyopathy (IDCM)40 or hypertrophic cardiomyopathy,41 and those with MVA31,42 or takotsubo syndrome.43
Importantly, TTDE has also been used to document the changes of CMV dilator function in response to drug therapy, in particular in patients with hypertension.38,39
Of note, a relation between reduced CFR assessed by TTDE and clinical outcome has been observed in preliminary studies in patients with dilated or hypertrophic cardiomyopathy.40,41 The utility of CMV function assessed by TTDE in predicting events in the different clinical settings, however, needs confirmation in larger studies.
Advantages and limitations
TTDE presents several advantages compared with other methods used for assessment of CMV function and CFR. It is totally noninvasive, easily available at bedside, not time consuming, cheap, and suitable for serial measurements to follow CMV function over time or check the effects of therapeutic interventions.
However, some important limitations of the method should be acknowledged. First, at present, there is sufficient evidence of its reliability only when CMV function is assessed in the LAD artery. Second, a valuable echographic window cannot be obtained in all patients. Third, the test requires appropriate experience by the operator.
Myocardial contrast echocardiography
Myocardial contrast echocardiography (MCE) is a noninvasive imaging technique, which exploits properties of intravenously administered microbubbles, which act as a contrast agent, to assess myocardial blood flow (MBF). On standard echocardiography, indeed, blood flow cannot usually be detected because red blood cells are very poor backscatters due to small dimensions and mild differences in acoustic impedance as compared to serum. Visualization of microbubbles is based on the peculiar ultrasound–bubble interaction. Because their dimension is smaller than the wavelength used in diagnostic echocardiography, microbubbles, such as red blood cells, would be unable to reflect transmitted ultrasound beam. However, they scatter ultrasound waves, producing a signal reliably detected by echocardiographic probes.44
Microbubbles are constituted by high molecular weight gases (nitrogen or fluorocarbon gas) encapsulated in a shell of phospholipids or albumin, and act as intravascular agents, as they do not cross the endothelial layer.44 When injected in a peripheral vein, microbubbles mix with blood and reach the right cardiac chambers. Then, due to their small sizes (1.1–8 μm), they freely pass throughout pulmonary capillaries and reach the left ventricular cavity and the coronary circulation, depicting the distribution of MBF.
When ultrasound energy, expressed as a mechanical index, is kept low within the diagnostic range, the scatter signal of microbubbles enhances detection of blood flow within the left ventricular cavity, but it is still too weak to be differentiated from the signal generated by the myocardial walls. By increasing the mechanical index, however, microbubbles begin to resonate, producing cycles of compression and rarefaction; this results in signals of low amplitude at a frequency (second harmonics) two times higher than the fundamental one, which can be detected by the probe and can therefore be processed to enable visualization of the myocardial blood pool.
Similarly to microspheres in the experimental setting, the signal derived from microbubbles is proportional to their concentration in the blood compartment. During continuous intravenous infusion, the signal is related to myocardial blood volume (MBV) and MBF. Accordingly, myocardial regions supplied by dysfunctional or damaged microcirculation appear as completely or partially not opacified (i.e. display perfusion defects).
Myocardial perfusion by MCE can be assessed by a semiquantitative method based on a scoring system, which grades each of 16 or 17 myocardial segments as 1, 2 or 3 when normal, reduced/delayed or absent opacification is seen, respectively. Furthermore, perfusion defects can be quantitated by measuring their endocardial length or transmural area and expressing them as a percentage of total endocardial border length or total myocardial wall area, respectively.
By plotting the curve of microbubble intensity over time, a quantitative measure of MBF can also be calculated as follows: y(t) = A (1 − e−βt), where y is the signal intensity, A is the plateau intensity (i.e. MBV), β reflects the rate of rise of intensity from microbubbles (hence, blood velocity), and t represents the pulsing interval. A reliable measure of MBF is provided by A × β.45 Measures of MBF by this method were found to be comparable to those obtained by PET.46 Of note, some software automatically encodes different grades of myocardial perfusion into various colors, thus providing a map of left ventricular perfusion.
To evaluate CMV dilator function by MCE, the contrast agent is given intravenously through an antecubital vein access, by continuous slow infusion (at the rate of 0.8–1 ml/min, depending on the concentration necessary to achieve the best compromise between clear visualization and avoidance of attenuation artifacts), which allows a better assessment of myocardial perfusion compared with bolus administration, which is instead usually sufficient for intracardiac shunt detection and intracavitary endocardial border delineation.
In the clinical setting, MCE has often been used to assess the state of coronary microcirculation in patients with acute myocardial infarction (AMI) undergoing successful recanalization of the infarct-related artery44,47–63 (Table 5).
The assessment of myocardial perfusion after successful percutaneous coronary intervention (PCI) aims at establishing the real effectiveness of the intervention. Indeed, it is now clear that an optimal recanalization of the infarct-related coronary artery does not always translate into an effective restoration of CBF at the microvascular level.64 This phenomenon, known as ‘no-reflow’, is caused by microvascular obstruction, which is the consequence of a complex series of events that include distal microembolization and ischemia/reperfusion injury of coronary microcirculation, with leukocyte plugging, red blood cell aggregates and vasospasm.65 When assessed by MCE, no-reflow appears as a black myocardial area localized within the dysfunctional segments (see above) (Fig. 4).
Thanks to the ability to easily repeat the test over time, MCE has contributed to clarify some important pathophysiological aspects of no-reflow. In particular, it has been demonstrated that no-reflow is a process characterized partly by structural and irreversible damage of coronary microcirculation and partly by functional abnormalities that may resolve over time. Indeed, about 50% of AMI patients exhibiting no-reflow after PCI show improvement in myocardial perfusion at 1 month follow-up, suggesting a relevant functional component of the microvascular damage. In the remaining 50% of the patients, however, no improvement is shown at follow-up, suggesting sustained, irreversible microvascular damage. Importantly, the persistence of perfusion defects predicts postinfarct left ventricular remodeling52 and a higher incidence of major adverse events,66 whereas recovery of myocardial perfusion parallels improvement of contractile function,51,67 reverse left ventricular remodeling68 and better outcome.
Importantly, a high agreement has been shown between MCE and cardiovascular magnetic resonance, as well as Tc-99m-sestamibi single-photon emission computed tomography (MIBI-SPECT),69 in detecting and quantifying the extent of no-reflow. Interestingly, quantitative measures of no-reflow by MCE appeared the most reliable predictors of postischemic left ventricular remodeling in a study.58
MCE has recently provided pathophysiological characterization of the takotsubo syndrome. Clinical presentation of this syndrome resembles that of an acute coronary syndrome, often with severe impairment of left ventricular function and ST-segment elevation.70 These patients, however, show normal coronary arteries at angiography, thus suggesting that microvascular abnormalities might be involved in the pathogenesis of the syndrome. MCE assessment of myocardial perfusion during the acute phase has indeed revealed large transmural perfusion defects within the dysfunctional area. Interestingly, adenosine administration during this phase produced a transient improvement of myocardial perfusion and function, thus suggesting that an intense constriction of coronary microcirculation is responsible for the perfusion defect and the severe myocardial dysfunction. Accordingly, at 1-week follow-up, normalization of myocardial perfusion was paralleled by recovery of left ventricular function63 (Fig. 5).
Finally, MCE has also contributed to confirm CMVD in patients with the stable form of MVA. Indeed, CFR assessed by both MCE and TTDE was significantly reduced in these patients as compared with controls, with a high correlation between the two methods.71
Advantages and limitations
Similar to TTDE, MCE is easy to perform and user-friendly for operators, with a favorable cost–effectiveness ratio. However, its wide application in clinical practice has been limited by safety issues following the report of some major adverse events occurring in a few critically ill patients after contrast administration, which urged the Food and Drug Administration and European Medicines Agency (EMEA) to forbid use of microbubbles in the cardiovascular arena.72 This black box warning was removed in April 2008, after excluding a strict cause–effect relation between microbubble injection and adverse clinical events. Nevertheless, EMEA warnings remain on the use of microbubbles in the acute phase of coronary syndromes, which may still limit the clinical application of MCE, although it continues to be safely applied in the research setting.
PET is a radionuclide technique that allows reproduction, using specific tracers, of tissue images that reflect specific functional aspects of a specific tissue.
Imaging with PET offers unrivalled sensitivity and specificity for studying noninvasively human pathophysiology in vivo. Cardiological research with PET has flourished over the past 20 years, but it is only more recently that cardiology has begun to benefit from the maximum efficiency of which PET is capable. From the physical point of view, scanning of the heart is more challenging because of greater complication in the correction for photon attenuation and scattered radiation and because of heart and respiratory motion.
The success of PET is founded on the properties of positron-emitting isotopes. Their short physical half-lives make it possible to administer a tracer dose high enough to obtain useful data, but such that the radiation burden to the patient is acceptably low. Positron emitters do not exist in nature and must be produced artificially by means of a particle accelerator (generally a cyclotron). Production of isotopes with the shortest half-lives has to be carried out in the vicinity of the scanner and necessitates the installation of cyclotron and radiochemistry facilities. However, 18F compounds can be delivered from a relatively remote site of production.
Positrons are emitted with a continuous range of energies up to a maximum, characteristic of each particular isotope. The positron is successively slowed down by Coulomb interaction with atomic electrons and annihilates with an electron when its energy has been reduced to close to zero, resulting in a pair of photons flying off in opposite directions with energy of 511 keV. Positrons emitted from a tracer injected into the body are not measured directly, but indirectly from the photons emitted when the positron annihilates with an electron. Detectors placed on both sides of the active volume are connected in a so-called coincidence circuit so that if both detectors record an event within a very short interval (about 10−8 s), it is assumed that a positron annihilation has taken place.73
PET has been shown to be a reliable tool to quantify MBF.74,75 The two tracers most widely used to measure MBF by PET are oxygen-15 labeled water (H215O)76–78 and nitrogen-13 labeled ammonia 13NH3.79–8113NH3 is administered intravenously as a bolus, whereas H215O can be given either intravenously, as a bolus injection or as a slow infusion, or by inhalation of oxygen-15 labeled carbon dioxide (C15O2), which is converted to H215O by carbonic anhydrase in the lungs.
Rubidium-82 (82Rb)82,83 was initially used for quantification of MBF. PET studies with 82Rb, however, are limited by the significant dependence of its myocardial extraction on flow rate and on myocardial metabolic state, which can make quantification of regional MBF less accurate, particularly during hyperemia and in metabolically impaired myocardium. In addition, the high positron energy of this radionuclide results in relatively poor image quality and a reduced spatial resolution.
Whereas PET cameras measuring MBF usually work in two-dimensional mode, the new generation of PET systems now available work in three-dimensional mode, with potential benefits, particularly in efficiency.84
PET studies have significantly contributed to characterize CMVD in several clinical settings. Relevant information has, in particular, been acquired in patients with cardiovascular risk factors. Smoking has been shown by PET to reduce adenosine-induced hyperemia by 17% and CFR by 21% compared with nonsmoking (P < 0.05). Interestingly, administration of the antioxidant vitamin C normalized coronary microcirculatory function, lending support to the hypothesis that the damaging effect of smoking can be explained, at least in part, by an increased oxidative stress (Fig. 6).85,86
PET studies have also confirmed the reduction of CFR in asymptomatic patients with hypercholesterolemia and shown how CMV function can be normalized by cholesterol-lowering strategies.86–88 Importantly, a relation has been found between CFR and low-density lipoprotein cholesterol subfraction, at least in those with high total cholesterol,89 supporting a direct pathogenic role of this subfraction in the development of CMVD.
Abnormal CFR has been demonstrated in several PET studies in patients with essential hypertension and angiographically normal coronary arteries.90–92 Importantly, these studies have clarified that the impairment of CFR in hypertensive patients is largely independent of the presence and degree of left ventricular hypertrophy,93 suggesting that CMVD is mainly a consequence of vascular remodeling or functional alterations of endothelial cells and/or SMCs.94,95 In addition, the abnormality of hyperemic MBF was found to be regionally heterogeneous in some patients, whereas the whole myocardium was involved in others.96
A PET study97 has also demonstrated a markedly impaired coronary microvascular vasodilation in response to adenosine and to CPT in young patients with uncomplicated diabetes, showing similar results in type 1 and type 2 diabetes, thus suggesting that hyperglycemia, rather than insulin sensitivity might be a major determinant of CMVD.
Clinically relevant results from PET studies have been obtained about the role of CMVD in patients with hypertrophic cardiomyopathy (HCM). Several studies98–101 have indeed demonstrated a marked impairment of the vasodilator response to dipyridamole, which usually diffusely involves the left ventricle, in agreement with the evidence at autopsy of widespread remodeling of intramural coronary arterioles.102,103 Accordingly, symptoms and signs of myocardial ischemia are often found in these patients despite the absence of epicardial artery lesions. Importantly, myocardial ischemia caused by CMVD in these patients might contribute to the most relevant complications of HCM, including ventricular arrhythmias and progressive impairment of systolic left ventricular function.102,103 Of note, a recent study has documented that the severity of CMVD, assessed by PET, was an independent predictor of long-term clinical deterioration and death from cardiovascular causes in these patients (Fig. 7).9
Also in patients with IDCM, an impaired MBF at rest and an impaired CFR104,105 have been demonstrated by PET studies. The impaired CMV dilator capacity has been shown to be an independent predictor of an increased risk of death and progression of heart failure (Fig. 8).8
Finally, PET has significantly contributed to characterize CMV function in patients with MVA. Although data have not always been concordant,106 several studies have shown a reduction in CMV dilation in response to both endothelium-independent and endothelium-dependent stimuli.107–110 Moreover, two studies have suggested the presence of intramyocardial heterogeneity in the impairment of CMV dysfunction, supporting the hypothesis of a nonuniform CMV alteration that might explain the difficulty in detecting left ventricular dysfunction during angina and ST-segment changes in these patients.109,110
Advantages and limitations
The most important advantage of PET in assessing CMV function is that it allows a reliable quantitative measure of MBF, both at rest and during vasoactive stimuli, thus allowing us to establish whether an impairment of vasodilator reserve is actually related to an impaired increase of MBF (i.e. to true CMVD), rather than to a basal increase in MBF, as can be seen in the hyperadrenergic state. A further merit of PET is the possibility to assess both global and regional CMV function.
Some limitations, however, need to be highlighted. First, the technique is expensive, time consuming and can only be performed in highly specialized centers. Accordingly, the technique is poorly available and poorly suitable for serial assessment of CMV function. Its resolution is less than optimal (about 5 mm), making detection of small areas of MBF abnormality difficult. Finally, the potential risk of radiation exposure should be considered, although the dose of radiation to which patients are exposed during MBF assessment with PET can be considered to be negligible.73
Cardiovascular magnetic resonance
MRI uses the property of resonance of nuclei of atoms exposed to a magnetic field to reconstruct images of the body. The application of powerful magnetic and radio frequency fields induces the nuclei to produce a rotating magnetic field that is detected by a scanner and used to reconstruct images of the scanned section. Magnetic fields of different nuclei rotate at different speeds, thus allowing accurate discrimination of different structures. Administration of paramagnetic contrast agents may improve discrimination of body tissues and organs.
The assessment of myocardial perfusion by cardiac magnetic resonance (CMR) is based on the changes in myocardial signal intensity of gadolinium, an extracellular contrast agent.111 After intravenous gadolinium injection, an ECG-gated acquisition of first-pass CMR images is obtained for the next 30–60 s, with the patients holding their breath to avoid interference motion with CMR image acquisition. Quantitative measurements of MBF (in units of ml/min per g of tissue) at rest and during hyperemia can be determined based on intensity curves of regions of interest.111
CMR has been used to assess CMVD in several clinical settings. In the Multi-Ethnic Study of Atherosclerosis, perfusion defects have been assessed in asymptomatic individuals with cardiovascular risk factors, although individuals selected also had evidence of coronary artery calcification.112
CMVD has also been documented by CMR in revascularized patients with coronary artery disease,113 those with takotsubo disease,114 and those with hypertrophic115 or dilated116 cardiomyopathy.
Significant CMV abnormalities have also been documented by CMR in patients with MVA. Panting et al.117 first showed an impairment of subendocardial CBF in response to adenosine. Lanza et al.118 have subsequently shown significant perfusion defects during dobutamine stress test in 56% of MVA patients, which correlated with a reduction of CBF response to adenosine as assessed by TTDE in the LAD coronary artery (Fig. 9).119
Finally, CMR has become the method of choice to identify and characterize areas of microvascular obstruction (‘no-reflow’) in patients with AMI undergoing successful recanalization of the infarct-related coronary artery. These areas can indeed be identified as hypoenhanced zones, suggesting CMV obstruction, in the context of the infarcted regions,120 and correlated with a worse clinical outcome121 (Fig. 10).122
Advantages and limitations
CMR perfusion imaging is characterized by high spatial resolution, lack of risk related to ionizing radiation and lack of attenuation-related problems (e.g. for breast shadow). Furthermore, the same examination allows assessment of not only perfusion but also global and regional myocardial contractility, as well as tissue morphology.119,123 Moreover, CMR allows an accurate evaluation of subendocardial and subepicardial perfusion, as well as of regional coronary resistance, in combination with the estimated diastolic perfusion time.122–124 Finally, by means of specific acquisition protocols, it is possible to visualize areas of postischemic edema of the left ventricle.123
Some important limitations, however, need to be acknowledged. To achieve an adequate signal-to-noise ratio of myocardial tissue enhancement, relatively large doses of gadolinium are needed. This affects the signal processing for MBF quantification, an issue that has only partially been resolved by using methods for nonlinear myocardial signal intensity correction.125 Concerns about toxicity of gadolinium-based contrast agents have also recently been highlighted, particularly in patients with chronic renal failure, in whom their use is associated with nephrogenic systemic fibrosis.126 Accordingly, gadolinium should not be used in patients with a glomerular filtration rate of 30 ml/min or less.
Postprocessing requires manual definition of myocardial regions of interest as well as of subendocardial and subepicardial areas, which can be time consuming and introduce some bias. Furthermore, during first pass, a fraction of gadolinium may diffuse into the interstitium; accordingly, myocardial signal intensity may depend not only on coronary perfusion but also on tissue blood volume, size of the extravascular compartment, and degree of capillary permeability, which can complicate quantitative assessment of MBF;127,128 to overcome these issues, however, specific models of signal analysis have been proposed and validated.129,130
Finally, some general conditions may preclude assessment of myocardial perfusion by CMR, including claustrophobia, arrhythmias and implanted devices.
Several invasive techniques have been proposed for the assessment of CMV function, although this is now predominantly assessed by intracoronary recording of CBF by Doppler and pressure wires.
This method is based on the indicator-dilution (Fick's) principle.131 Briefly, cold saline is infused into the coronary sinus at a known temperature and rate and blood temperature is measured downstream. The dilution of the tracer is indicated by the reduction in blood temperature, which is proportional to CBF and can therefore be calculated. This method only allows measurement of the whole CBF. However, if the procedure is performed in the great cardiac vein, CBF in the anterior ventricular wall (almost exclusively perfused by the LAD coronary artery) can be measured.131
Importantly, intracoronary thermodilution can now be performed using intracoronary wires that incorporate thermal sensors. In this case, a 3-ml bolus of room-temperature saline is injected into a coronary artery; the entry of saline is registered by a shaft thermistor over the wire while a distal sensor captures the resulting temperature shift. The mean transit time (mTT) of the indicator is calculated, which is inversely proportional to CBF. CFR, in this case, is calculated as the ratio between the resting mTT and hyperemic mTT.132,133
Thermodilution methods present some drawbacks. Stable positioning of the catheter, especially in the coronary sinus, can be difficult and quantification of flow requires accurate recording of temperature and volume of the indicator at the injection and the distal site, which can often be problematic and display relatively high variability, also due to frequent incomplete mixing of saline and blood.
Gas washout method
This method134 is also based on the indicator-dilution principle, but uses an inert gas as a tracer (usually argon or xenon). Again, the change in the coronary sinus of the gas concentration from the site of injection to that recorded downstream allows calculation of CBF.
The gas, as a radioactive tracer, can also be inhaled at a known concentration over a 5-min period. Analyses of gas concentrations by gas chromatography in arterial (coronary) and coronary sinus blood samples allow calculation of CBF, as this is proportional to tissue concentration of the gas divided by its mean artery-coronary sinus difference. Alternatively, the gas can be injected directly into the coronary arteries. These methods can also allow assessment of regional CBF, based on the scintigraphic detection of activity of the radio-labeled gas. However, the latter approach has major limitations in several clinical conditions.
Intracoronary Doppler flow wire
Intracoronary Doppler wires allow direct measurement of CBF velocity in single epicardial arteries, based on the Doppler effect, which establishes that the velocity and direction of blood flow can be derived by determining the frequency shift resulting from the emitted and the returning ultrasound waves, according to the Doppler equation.135
Intracoronary Doppler wires can incorporate a pressure sensor that allows measurement of intracoronary blood pressure. The product of CBF velocity and the section area of the vessel gives a measure of CBF.
Although CBF velocity measurements from Doppler signals are robust, determination of the cross-sectional area of the vessel for calculations of CBF remains problematic even with quantitative coronary angiography. However, this issue is of limited relevance in the case of normal coronary arteries, due to the usually limited variations of epicardial vessels during administration of vasodilator stimuli for the assessment of CFR.
Technical problems may also impair the correct acquisition of the signal, including guiding catheter obstruction to flow, poor zeroing/calibration and signal loss. Additionally, suboptimal guide catheter engagement may result in inadequate delivery of vasodilator agents, thus limiting the accuracy of CFR. Technical artifacts of signal acquisition must be recognized and then minimized to obtain reliable flow data.
Other invasive indexes of coronary microvascular function
Some specific characteristics of the Doppler velocity waveform have also been used to deduce information about microvascular injury. In particular, the deceleration time of diastolic flow (DDT) reflects the compliance of the microvascular compartment. Rapid flow deceleration can indeed be regarded as a sign of increased coronary microvascular resistance, suggesting (pre)-arteriolar constriction.136
Measurement of coronary resistance can more easily be added to that of CBF during invasive tests to better characterize CMV function. Coronary resistance can be measured at rest and at peak hyperemia (hyperemic microvascular resistance), thus obtaining a measure of its reduction during maximal vasodilation.137,138 It can be calculated using the formula:
where MAP is the mean aortic pressure and RAP the right atrial pressure. However, the calculation can in most cases be reliably simplified as the ratio of coronary DBP to average peak flow velocity.
Coronary resistance has also been proposed to be estimated by the index of microvascular resistance, defined as the product of coronary pressure by the hyperemic mTT (which is inversely correlated to absolute flow, as measured simultaneously with the coronary pressure wire).137–139
To circumvent the issue of cross-sectional area imaging, a similar index of resistance has been introduced, the velocity-based index of CMVR, which is calculated as the ratio between central arterial pressure and Doppler CBF velocity and expressed in mmHg/cm per s.140
An increased corrected Thrombolysis in Myocardial Infarction frame count of contrast agent during coronary angiography141 and a higher blush grade142 have both been considered as a rough, but sufficiently reliable, expression of increased coronary microvascular constriction. These methods provide a semiquantitative categorization of CBF, with the implicit assumption that, in the absence of significant stenosis, a slow flow in epicardial vessels and a lower opacification of myocardium, respectively, would reflect an impairment of coronary microcirculation.
Finally, a direct assessment of CMV function during catheterization might also be obtained by the use of a first-pass distribution analysis (FPA) technique. This method measures the absolute CBF on angiographic images through densitometric analysis of spatial and temporal aspects of the contrast propagation through the myocardium.143,144 The FPA technique would be an easy-to-implement method, which might be also done in conjunction with routine coronary angiography. The method, however, has until now been applied and validated only in animal models, and, therefore, its reliability in humans needs to be addressed before it can be recommended for use in clinical practice.
Invasive methods have until recently been the only kind of tests that could be used to reliably assess CMV function, and they have given an outstanding contribution in identifying and characterizing CMVD in several clinical settings. In particular, the ICDW technique has become the most widely used invasive method to explore the state of coronary microcirculation. Of note, invasive studies allow the investigation not only of CMV dilator function but also of CMV response to constrictor stimuli.
Invasive methods have been used to assess CMV function in patients with the no-reflow phenomenon after primary coronary revascularization in the acute phase of myocardial infarction, showing a dramatic reduction in CFR, which has also been shown to predict a worse clinical prognosis.145–148 Intracoronary Doppler studies have also contributed to document CMVD in patients with either dilated149 or hypertrophic cardiomyopathy,150 as well as in patients with takotsubo disease.151
An impairment of both endothelium-independent and endothelium-dependent CMV dilation in patients with MVA has also been demonstrated by invasive studies152–155 (Fig. 11), whereas some other reports have documented an increased constrictor response to vasoactive stimuli in these patients.156
Finally, intracoronary Doppler recordings have given a crucial contribution in characterizing the impairment of CMV function detectable in the territory of stenotic epicardial coronary arteries treated by PCIs.157
Advantages and limitations
When performed carefully, invasive methods allow the most accurate assessment of CMV dilator function. They indeed allow intracoronary injection of pharmachological stimuli, such as adenosine, with the possibility to achieve maximal CMV dilatation with appropriate doses without affecting blood pressure, which might instead be reduced with the systemic administration of the vasodilator substance, with consequences on myocardial perfusion and the correct assessment of CFR. Furthermore, only invasive methods allow a reliable assessment of CMV response to vasoconstrictor stimuli, as they may be integrated with angiography to exclude significant epicardial vasoconstriction.
The most reliable invasive methods to investigate CMV function are based on intracoronary Doppler recording. An advantage of this method is that it allows a separate assessment of CBF in the different coronary artery territories. The use of intracoronary thermodilution also seems reliable and data about CFR are comparable to those of intracoronary Doppler measures.132
Invasive methods, however, have inevitable limitations. They are more expensive compared with most noninvasive methods; they are also time consuming, which is often incompatible with the busy routine activity of most cath-labs, cannot easily been repeated serially, and portend a possible increase in serious adverse events.
In this article, we have briefly reviewed the available methods of investigating CMV function in patients without any significant obstruction of epicardial coronary arteries. A comparative summary of these methods is shown in Table 6.
The optimal method for investigation of CMV function should be largely available, easy to perform, not expensive, without risks, reliable and reproducible. None of the available methods, however, fulfill all these ideal characteristics.
Invasive methods, in particular intracoronary Doppler recording, remain the most reliable for CMV function assessment, as they allow direct measurements and control for several potentially confounding variables. Furthermore, only invasive techniques allow the reliable assessment of the response of coronary microcirculation to constrictor stimuli. However, costs, prolongation of invasive procedures and potential risks make these methods unsuitable for clinical routine use, and even for most research studies that require serial measurements.
Sophisticated and technologically advanced noninvasive methods, such as PET and CMR, are now available to assess CMV function. These methods appear very reliable, with potential large margins for further improvement in the near future, and they might be considered as reference tests for most research studies. However, low availability, high costs and some potential risks significantly limit their routine use for CMV studies.
A promising method is represented by contrast echocardiography, which is easier to perform and more widely available. Further studies, however, seem necessary to exclude some appreciable risks related to contrast agents and to better establish the reliability and reproducibility of quantitative measurements of CBF.
Finally, TTDE is the most simple, widely available, cheap and safe technique, but it presents significant limitations due to some technical difficulties and to the fact that it is, to a large extent, operator-dependent. Furthermore, it may limit the examination to the LAD coronary artery territory only in most cases. Yet, in clinical practice, it might constitute the first screening test to identify patients with significant impairment of CMV function, followed, as a second step, by CMR in patients in whom it is inconclusive or in whom a more accurate assessment of CMV function is required, with MCE or PET being possible alternatives in selected cases and/or in experienced centers.
1. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med
2. Lanza GA, Crea F. Primary coronary microvascular dysfunction: clinical presentation, pathophysiology, and management. Circulation
3. Maseri A. Ischemic heart disease. New York: Churchill Livingstone; 1995.
4. Kaski JC, Rosano GMC, Collins P, et al. Cardiac syndrome X: clinical characteristics and left ventricular function. Long-term follow-up study. J Am Coll Cardiol
5. Lamendola P, Lanza GA, Spinelli A, et al. Long-term prognosis of patients with cardiac syndrome X. Int J Cardiol
6. Bugiardini R, Bairey Merz CN. Angina with ‘normal’ coronary arteries: a changing philosophy. JAMA
7. Bugiardini R, Manfrini O, De Ferrari GM. Unanswered questions for management of acute coronary syndrome: risk stratification of patients with minimal disease or normal findings on coronary angiography. Arch Intern Med
8. Neglia D, Michelassi C, Trivieri MG, et al. Prognostic role of myocardial blood flow impairment in idiopathic left ventricular dysfunction. Circulation
9. Cecchi F, Olivotto I, Gistri R, et al. Coronary microvascular dysfunction and prognosis in hypertrophic cardiomyopathy. N Engl J Med
10. Escaned J, Flores A, García-Pavía P, et al. Assessment of microcirculatory remodeling with intracoronary flow velocity and pressure measurements: validation with endomyocardial sampling in cardiac allografts. Circulation
11. Pizzi C, Bugiardini R. Further insights into syndrome X. Heart
12. Leung DY, Leung M. Noninvasive/invasive imaging: significance and assessment of coronary microvascular dysfunction. Heart
13. Marzilli M, Sambuceti G, Fedele S, L’Abbate A. Coronary microcirculatory vasoconstriction during ischemia in patients with unstable angina. J Am Coll Cardiol
14. Pries AR, Habazettl H, Ambrosio G, et al. A review of methods for assessment of coronary microvascular disease in both clinical and experimental settings. Cardiovasc Res
15. Webb CM, Collins P, Di Mario C. Normal coronary physiology assessed by intracoronary Doppler ultrasound
16. McGuinness ME, Talbert RL. Pharmacologic stress testing: experience with dipyridamole, adenosine, and dobutamine. Am J Hosp Pharm
17. Münzel T, Sinning C, Post F, et al. Pathophysiology diagnosis and prognostic implications of endothelial dysfunction. Ann Med
18. Bugiardini R, Badimon L, Collins P, et al. Angina ‘normal’ coronary angiography, and vascular dysfunction: risk assessment strategies. PLoS Med
19. Sanderson JE, Woo KS, Chung HK, et al. Endothelium-dependent dilation of the coronary arteries in syndrome X: effects of the cold pressor test. Cardiology
20. Kiviniemi T. Assessment of coronary blood flow and the reactivity of the microcirculation noninvasively with transthoracic echocardiography. Clin Physiol Funct Imaging
21. Meimoun P, Tribouilloy C. Noninvasive assessment of coronary flow and coronary flow reserve by transthoracic Doppler echocardiography
: a magic tool for the real world. Eur J Echocardiogr
22. Pizzuto F, Voci P, Mariano E, et al. Assessment of flow velocity reserve by transthoracic Doppler echocardiography
and venous adenosine infusion before and after left anterior descending coronary artery stenting. J Am Coll Cardiol
23. Galderisi M, Cicala S, D’Errico A, et al. Nebivolol improves coronary flow reserve in hypertensive patients without coronary heart disease. J Hypertens
24. Hozumi T, Yoshida K, Akasaka T, et al. Noninvasive assessment of coronary flow velocity and coronary flow velocity reserve in the left anterior descending coronary artery by Doppler echocardiography: comparison with invasive technique. J Am Coll Cardiol
25. Hildick-Smith DJ, Maryan R, Shapiro LM. Assessment of coronary flow reserve by adenosine transthoracic echocardiography: validation with intracoronary Doppler. J Am Soc Echocardiogr
26. Lethen H, Tries HP, Brechtken J, et al. Comparison of transthoracic Doppler echocardiography
to intracoronary Doppler guidewire measurements for assessment of coronary flow reserve in the left anterior descending artery for detection of restenosis after coronary angioplasty. Am J Cardiol
27. Ueno Y, Nakamura Y, Takashima H, et al. Noninvasive assessment of coronary flow velocity and coronary flow velocity reserve in the right coronary artery by transthoracic Doppler echocardiography
: comparison with intracoronary Doppler guidewire. J Am Soc Echocardiogr
28. Lethen H, P Tries H, Kersting S, Lambertz H. Validation of noninvasive assessment of coronary flow velocity reserve in the right coronary artery. A comparison of transthoracic echocardiographic results with intracoronary Doppler flow wire measurements. Eur Heart J
29. Auriti A, Pristipino C, Cianfrocca C, et al
. Distal left circumflex coronary artery flow reserve recorded by transthoracic Doppler echocardiography
: a comparison with Doppler-wire. Cardiovasc Ultrasound
30. Saraste M, Koskenvuo J, Knuuti J, et al. Coronary flow reserve: measurement with transthoracic Doppler echocardiography
is reproducible and comparable with positron emission tomography. Clin Physiol
31. Sestito A, Lanza GA, Di Monaco A, et al. Relation between cardiovascular risk factors and coronary microvascular dysfunction in cardiac syndrome X. J Cardiovasc Med (Hagerstown)
32. Otsuka R, Watanabe H, Hirata K, et al. Acute effects of passive smoking on the coronary circulation in healthy young adults. JAMA
33. Hozumi T, Eisenberg M, Sugioka K, et al. Change in coronary flow reserve on transthoracic Doppler echocardiography
after a single high-fat meal in young healthy men. Ann Intern Med
34. Kiviniemi TO, Toikka JO, Koskenvuo JW, et al. Vasodilation of epicardial coronary artery can be measured with transthoracic echocardiography. Ultrasound Med Biol
35. Oe H, Hozumi T, Murata E, et al. Arachidonic acid and docosahexaenoic acid supplementation increases coronary flow velocity reserve in Japanese elderly individuals. Heart
36. Khan F, Patterson D, Belch JJ, et al. Relationship between peripheral and coronary function using laser Doppler imaging and transthoracic echocardiography. Clin Sci (Lond)
37. Shiina Y, Funabashi N, Lee K, et al. Acute effect of oral flavonoid-rich dark chocolate intake on coronary circulation, as compared with nonflavonoid white chocolate, by transthoracic Doppler echocardiography
in healthy adults. Int J Cardiol
38. Lethen H, Tries HP, Kersting S, et al. Improvement of coronary microvascular function after angiotensin receptor blocker treatment with irbesartan in patients with systemic hypertension. J Clin Hypertens (Greenwich)
39. Zhang X, Yang Y, Li Z, et al. Noninvasive evaluation of coronary flow velocity reserve in homozygous familial hypercholesterolemia by transthoracic Doppler echocardiography
40. Rigo F, Gherardi S, Galderisi M, et al. The prognostic impact of coronary flow-reserve assessed by Doppler echocardiography in nonischaemic dilated cardiomyopathy. Eur Heart J
41. Cortigiani L, Rigo F, Gherardi S, et al. Prognostic implications of coronary flow reserve on left anterior descending coronary artery in hypertrophic cardiomyopathy. Am J Cardiol
42. Di Monaco A, Bruno I, Sestito A, et al. Cardiac adrenergic nerve function and microvascular dysfunction in patients with cardiac syndrome X. Heart
43. Barletta G, Del Pace S, Boddi M, et al. Abnormal coronary reserve and left ventricular wall motion during cold pressor test in patients with previous left ventricular ballooning syndrome. Eur Heart J
44. Senior R, Becher H, Monaghan M, et al. Contrast echocardiography: evidence-based recommendations by European Association of Echocardiography. Eur J Echocardiogr
45. Wein K, Jayaweera AR, Firoozan S, et al. Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation
46. Muro T, Hozumi T, Watanabe H, et al. Assessment of myocardial perfusion abnormalities by intravenous myocardial contrast echocardiography
with harmonic power Doppler imaging: comparison with positron emission tomography. Heart
47. Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation
48. Ito H, Tomooka T, Sakai N, et al. Time course of functional improvement in stunned myocardium in risk area in patients with reperfused anterior infarction. Circulation
49. Kamp O, Lepper W, Vanoverschelde JL, et al. Serial evaluation of perfusion defects in patients with a first acute myocardial infarction referred for primary PTCA using intravenous myocardial contrast echocardiography
. Eur Heart J
50. Balcells E, Powers ER, Lepper W, et al. Detection of myocardial viability by contrast echocardiography in acute infarction predicts recovery of resting function and contractile reserve. J Am Coll Cardiol
51. Galiuto L, Lombardo A, Maseri A, et al. Temporal evolution and functional outcome of no reflow: sustained and spontaneously reversible patterns following successful coronary recanalisation. Heart
52. Bolognese L, Carrabba N, Parodi G, Santoro GM. Impact of microvascular dysfunction on left ventricular remodeling and long-term clinical outcome after primary coronary angioplasty for acute myocardial infarction. Circulation
53. Agati L, Tonti G, Pedrizzetti G, et al. Clinical application of quantitative analysis in real-time MCE. Eur J Echocardiogr
54. Janardhanan R, Moon JC, Pennell DJ, Senior R. Myocardial contrast echocardiography
accurately reflects transmurality of myocardial necrosis and predicts contractile reserve after acute myocardial infarction. Am Heart J
55. Moir S, Haluska BA, Jenkins C, et al. Myocardial blood volume and perfusion reserve responses to combined dipyridamole and exercise stress: a quantitative approach to contrast stress echocardiography. J Am Soc Echocardiogr
56. Galiuto L, Garramone B, Burzotta F, et al. REMEDIA Investigators. Thrombus aspiration reduces microvascular obstruction after primary coronary intervention: a myocardial contrast echocardiography
substudy of the REMEDIA Trial. J Am Coll Cardiol
57. Trindade ML, Caldas MA, Tsutsui JM, et al. Determination of size and transmural extent of acute myocardial infarction by real-time myocardial perfusion echocardiography: a comparison with magnetic resonance imaging. J Am Soc Echocardiogr
58. Galiuto L, Garramone B, Scarà A, et al. AMICI Investigators. The extent of microvascular damage during myocardial contrast echocardiography
is superior to other known indexes of postinfarct reperfusion in predicting left ventricular remodeling: Results of the multicenter AMICI study. J Am Coll Cardiol
59. Abdelmoneim SS, Bernier M, Dhoble A, et al. Assessment of the vascularity of a left atrial mass using myocardial perfusion contrast echocardiography. Echocardiography
60. Hayat SA, Dwivedi G, Jacobsen A, et al. Effects of left bundle-branch block on cardiac structure, function, perfusion, and perfusion reserve: implications for myocardial contrast echocardiography
versus radionuclide perfusion imaging for the detection of coronary artery disease. Circulation
61. Senior R, Monaghan M, Main ML, et al. RAMP-1 and RAMP-2 Investigators. Detection of coronary artery disease with perfusion stress echocardiography using a novel ultrasound imaging agent: two Phase 3 international trials in comparison with radionuclide perfusion imaging. Eur J Echocardiogr
62. Mansencal N, Revault-d’Allonnes L, Pelage JP, et al. Usefulness of contrast echocardiography for assessment of intracardiac masses. Arch Cardiovasc Dis
63. Galiuto L, De Caterina AR, Porfidia A, et al. Reversible coronary microvascular dysfunction: a common pathogenetic mechanism in Apical Ballooning or Tako-Tsubo Syndrome. Eur Heart J
64. Galiuto L, DeMaria AN, May-Newman K, et al. Evaluation of dynamic changes in microvascular flow during ischemia-reperfusion by myocardial contrast echocardiography
. J Am Coll Cardiol
65. Niccoli G, Burzotta F, Galiuto L, Crea F. Myocardial no-reflow in humans. J Am Coll Cardiol
66. Ito H, Maruyama A, Iwakura K, et al. Clinical implications of the no-reflow phenomenon. A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation
67. Galiuto L. Optimal therapeutic strategies in the setting of postinfarct no re-flow: the need for a pathogenetic classification. Heart
68. Funaro S, La Torre G, Madonna M, et al. AMICI Investigators. Incidence, determinants, and prognostic value of reverse left ventricular remodelling after primary percutaneous coronary intervention: results of the Acute Myocardial Infarction Contrast Imaging (AMICI) multicenter study. Eur Heart J
69. Lombardo A, Rizzello V, Galiuto L, et al. Assessment of resting perfusion defects in patients with acute myocardial infarction: comparison of myocardial contrast echocardiography
, combined first-pass/delayed contrast-enhanced magnetic resonance imaging and 99mTC-sestamibi SPECT. Int J Cardiovasc Imaging
70. Bielecka-Dabrowa A, Mikhailidis DP, Hannam S, et al. Takotsubo cardiomyopathy: the current state of knowledge. Int J Cardiol
71. Galiuto L, Sestito A, Barchetta S, et al. Noninvasive evaluation of flow reserve in the left anterior descending coronary artery in patients with cardiac syndrome X. Am J Cardiol
72. Grayburn PA. ‘Product safety’ compromises patient safety (an unjustified black box warning on ultrasound contrast agents by the Food and Drug Administration). Am J Cardiol
73. Peng BH, Levin CS. Recent development in PET
instrumentation. Curr Pharm Biotechnol
74. Kaufmann PA, Camici PG. Myocardial blood flow by PET
: technical aspects and clinical applications. J Nucl Med
75. Camici PG, Rimoldi OE. The clinical value of myocardial blood flow measurement. J Nucl Med
76. Bergmann SR, Herrero P, Markham J, et al. Noninvasive quantitation of myocardial blood flow in human subjects with oxygen-15-labeled water and positron emission tomography. J Am Coll Cardiol
77. Araujo LI, Lammertsma AA, Rhodes CG, et al. Noninvasive quantification of regional myocardial blood flow in coronary artery disease with oxygen-15-labeled carbon dioxide inhalation and positron emission tomography. Circulation
78. Kaufmann PA, Gnecchi-Ruscone T, Yap JT, et al. Assessment of the reproducibility of baseline and hyperemic myocardial blood flow measurements with 15O-labeled water and PET
. J Nucl Med
79. Bellina CR, Parodi O, Camici P, et al. Simultaneous in vitro and in vivo validation of nitrogen-13-ammonia for the assessment of regional myocardial blood flow. J Nucl Med
80. Hutchins GD, Schwaiger M, Rosenspire KC, et al. Noninvasive quantification of regional blood flow in the human heart using N-13 ammonia and dynamic positron emission tomographic imaging. J Am Coll Cardiol
81. Krivokapich J, Smith GT, Huang SC, et al. 13N ammonia myocardial imaging at rest and with exercise in normal volunteers. Quantification of absolute myocardial perfusion with dynamic positron emission tomography. Circulation
82. Herrero P, Markham J, Shelton ME, et al. Noninvasive quantification of regional myocardial perfusion with rubidium-82 and positron emission tomography. Exploration of a mathematical model. Circulation
83. Scott NS, Le May MR, de Kemp R, et al. Evaluation of myocardial perfusion using rubidium-82 positron emission tomography after myocardial infarction in patients receiving primary stent implantation or thrombolytic therapy. Am J Cardiol
84. Schäfers KP, Spinks TJ, Camici PG, et al. Absolute quantification of myocardial blood flow with H(2)(15)O and 3-dimensional PET
: an experimental validation. J Nucl Med
85. Kaufmann PA, Gnecchi-Ruscone T, di Terlizzi M, et al. Coronary heart disease in smokers: vitamin C restores coronary microcirculatory function. Circulation
86. Tamai O, Matsuoka H, Itabe H, et al. Single LDL apheresis improves endothelium-dependent vasodilation in hypercholesterolemic humans. Circulation
87. Gould KL, Martucci JP, Goldberg DI, et al. Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease. Circulation
88. Yokoyama I, Ohtake T, Momomura S, et al. Reduced coronary flow reserve in hypercholesterolemic patients without overt coronary stenosis. Circulation
89. Kaufmann PA, Gnecchi-Ruscone T, Schafers KP, et al. Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia. J Am Coll Cardiol
90. Strauer BE. Ventricular function and coronary hemodynamics in hypertensive heart disease. Am J Cardiol
91. Opherk D, Mall G, Zebe H, et al. Reduction of coronary reserve: a mechanism for angina pectoris in patients with arterial hypertension and normal coronary arteries. Circulation
92. Brush JE Jr, Cannon RO 3rd, Schenke WH, et al. Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. N Engl J Med
93. Vogt M, Motz W, Strauer BE. Coronary haemodynamics in hypertensive heart disease. Eur Heart J
1992; 13 (Suppl D):44–49.
94. Tanaka M, Fujiwara H, Onodera T, et al. Quantitative analysis of narrowing of intramyocardial small arteries in normal heart, hypertensive hearts, and hearts with hypertrophic cardiomyopathy. Circulation
95. Schwartzkopff B, Motz W, Frenzel H, et al. Structural and functional alterations of the intramyocardial coronary arterioles in patients with arterial hypertension. Circulation
96. Gimelli A, Schneider-Eicke J, Neglia D, et al. Homogeneously reduced versus regionally impaired myocardial blood flow in hypertensive patients: two different patterns of myocardial perfusion associated with degree of hypertrophy. J Am Coll Cardiol
97. Di Carli MF, Janisse J, Grunberger G, Ager J. Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in diabetes. J Am Coll Cardiol
98. Camici P, Chiriatti G, Lorenzoni R, et al. Coronary vasodilation is impaired in both hypertrophied and nonhypertrophied myocardium of patients with hypertrophic cardiomyopathy: a study with nitrogen-13 ammonia and positron emission tomography. J Am Coll Cardiol
99. Camici PG, Cecchi RG, Montereggi A, et al. Dipyridamole-induced subendocardial underperfusion in hypertrophic cardiomyopathy assessed by positron-emission tomography. Coron Art Dis
100. Gistri R, Cecchi F, Choudhury L, et al. Effect of verapamil on absolute myocardial blood flow in hypertrophic cardiomyopathy. Am J Cardiol
101. Choudhury L, Elliott P, Rimoldi O, et al. Transmural myocardial blood flow distribution in hypertrophic cardiomyopathy and effect of treatment. Basic Res Cardiol
102. Basso C, Thiene G, Corrado D, et al. Hypertrophic cardiomyopathy and sudden death in the young: pathologic evidence of myocardial ischemia. Hum Pathol
103. Maron BJ, Wolfson JK, Epstein SE, Roberts WC. Intramural (‘small vessel’) coronary artery disease in hypertrophic cardiomyopathy. J Am Coll Cardiol
104. Neglia D, Parodi O, Gallopin M, et al. Myocardial blood flow response to pacing tachycardia and to dipyridamole infusion in patients with dilated cardiomyopathy without overt heart failure. A quantitative assessment by positron emission tomography. Circulation
105. Canetti M, Akhter MW, Lerman A, et al. Evaluation of myocardial blood flow reserve in patients with chronic congestive heart failure due to idiopathic dilated cardiomyopathy. Am J Cardiol
106. Rosen SD, Uren NG, Kaski JC, et al. Coronary vasodilator reserve, pain perception, and sex in patients with syndrome X. Circulation
107. Bøttcher M, Botker HE, Sonne H, et al. Endothelium-dependent and -independent perfusion reserve and the effect of L-arginine on myocardial perfusion in patients with syndrome X. Circulation
108. de Vries J, DeJongste MJ, Jessurun GA, et al. Myocardial perfusion quantification in patients suspected of cardiac syndrome X with positive and negative exercise testing: a [13N]ammonia positron emission tomography study. Nucl Med Commun
109. Meeder JG, Blanksma PK, van der Wall EE, et al. Coronary vasomotion in patients with syndrome X: evaluation with positron emission tomography and parametric myocardial perfusion imaging. Eur J Nucl Med
110. Galassi AR, Crea F, Araujo LI, et al. Comparison of regional myocardial blood flow in syndrome X and one-vessel coronary artery disease. Am J Cardiol
111. Jerosch-Herold M, Seethamraju RT, Swingen CM, et al. Analysis of myocardial perfusion MRI. J Magn Reson Imaging
112. Rosen BD, Lima JA, Nasir K, et al. Lower myocardial perfusion reserve is associated with decreased regional left ventricular function in asymptomatic participants of the multiethnic study of atherosclerosis. Circulation
113. Patel AR, Epstein FH, Kramer CM. Evaluation of the microcirculation: advances in cardiac magnetic resonance perfusion imaging. J Nucl Cardiol
114. Avegliano G, Huguet M, Costabel JP, et al. Morphologic pattern of late gadolinium enhancement in Takotsubo cardiomyopathy detected by early cardiovascular magnetic resonance
. Clin Cardiol
115. Petersen SE, Jerosch-Herold M, Hudsmith LE, et al. Evidence for microvascular dysfunction in hypertrophic cardiomyopathy: new insights from multiparametric magnetic resonance imaging. Circulation
116. Hombach V, Merkle N, Torzewski J, et al. Electrocardiographic and cardiac magnetic resonance imaging parameters as predictors of a worse outcome in patients with idiopathic dilated cardiomyopathy. Eur Heart J
117. Panting JR, Gatehouse PD, Yang GZ, et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance
imaging. N Engl J Med
118. Lanza GA, Buffon A, Sestito A, et al. Relation between stress-induced myocardial perfusion defects on cardiovascular magnetic resonance
and coronary microvascular dysfunction in patients with cardiac syndrome X. J Am Coll Cardiol
119. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation
120. Esposito G, Dellegrottaglie S, Chiariello M. The extent of irreversible myocardial damage and the potential for left ventricular repair after primary percutaneous coronary intervention. Am Heart J
2010; 160 (6 Suppl):S4–S10.
121. Hombach V, Merkle N, Bernhard P, et al. Prognostic significance of cardiac magnetic resonance imaging: Update 2010. Cardiol J
122. Plein S, Kozerke S, Suerder D, et al. High spatial resolution myocardial perfusion cardiac magnetic resonance for the detection of coronary artery disease. Eur Heart J
123. Raman SV, Simonetti OP, Winner MW III, Ambrosio G. Cardiac magnetic resonance with edema imaging identifies myocardium at risk and predicts worse outcome in patients with non–ST-segment elevation acute coronary syndrome. J Am Coll Cardiol
124. Plein S, Schwitter J, Suerder D, Kozerke S. k-Space and time sensitivity encoding accelerated myocardial perfusion MR imaging at 3.0 T: comparison with 1.5 T. Radiology
125. Hsu LY, Kellman P, Arai AE. Nonlinear myocardial signal intensity correction improves quantification of contrast-enhanced first-pass MR perfusion in humans. J Magn Reson Imaging
126. Kuo PH, Kanal E, Abu-Alfa AK, Cowper SE. Gadolinium-based MR contrast agents and nephrogenic systemic fibrosis. Radiology
127. Tong CY, Prato FS, Wisenberg G, et al. Techniques for the measurement of the local myocardial extraction efficiency for inert diffusible contrast agents such as gadopentate dimeglumine. Magn Reson Med
128. Tong CY, Prato FS, Wisenberg G, et al. Measurement of the extraction efficiency and distribution volume for Gd-DTPA in normal and diseased canine myocardium. Magn Reson Med
129. Zierler K. Indicator dilution methods for measuring blood flow, volume, and other properties of biological systems: a brief history and memoir. Ann Biomed Eng
130. Jerosch-Herold M, Swingen C, Seethamraju RT. Myocardial blood flow quantification with MRI by model-independent deconvolution. Med Phys
131. Marcus ML, Wilson RF, White CW. Methods of measurement of myocardial blood flow in patients: a critical review. Circulation
132. Pijls NH, De Bruyne B, Smith L, et al. Coronary thermodilution to assess flow reserve: validation in humans. Circulation
133. Melikian N, Kearney MT, Thomas MR, et al. A simple thermodilution technique to assess coronary endothelium-dependent microvascular function in humans: validation and comparison with coronary flow reserve. Eur Heart J
134. Kelm M, Strauer BE. Coronary flow reserve measurements in hypertension. Med Clin North Am
135. Joye JD, Schulman DS. Clinical application of coronary flow reserve using an intracoronary Doppler guide wire. Cardiol Clin
136. Tahk SJ, Choi BJ, Choi SY, et al. Distal protection device protects microvascular integrity during primary percutaneous intervention in acute myocardial infarction: a prospective, randomized, multicenter trial. Int J Cardiol
137. Spaan JA, Piek JJ, Hoffman JI, Siebes M. Physiological basis of clinically used coronary hemodynamic indices. Circulation
138. Knaapen P, Camici PG, Marques KM, et al. Coronary microvascular resistance: methods for its quantification in humans. Basic Res Cardiol
139. Fearon WF, Balsam LB, Farouque HM, et al. Novel index for invasively assessing the coronary microcirculation
140. Kolyva C, Spaan JA, Piek JJ, Siebes M. Windkesselness of coronary arteries hampers assessment of human coronary wave speed by single-point technique. Am J Physiol Heart Circ Physiol
141. Gibson CM, Murphy S, Menown IB, et al
. Determinants of coronary blood flow after thrombolytic administration. TIMI Study Group. Thrombolysis in Myocardial Infarction. J Am Coll Cardiol
142. Molloi S, Ersahin A, Tang J, et al. Quantification of volumetric coronary blood flow with dual-energy digital subtraction angiography. Circulation
143. Zhang Z, Takarada S, Molloi S. Quantification of coronary microvascular resistance using angiographic images for volumetric blood flow measurement: in vivo validation. Am J Physiol Heart Circ Physiol
144. Porto I, Hamilton-Craig C, Brancati M, et al. Angiographic assessment of microvascular perfusion: myocardial blush in clinical practice. Am Heart J
145. Manfrini O, Pizzi C, Morgagni G, et al. Effect of pravastatin on myocardial perfusion after percutaneous transluminal coronary angioplasty. Am J Cardiol
146. Valgimigli M, Campo G, Malagutti P, et al. Persistent coronary no flow after wire insertion is an early and readily available mortality risk factor despite successful mechanical intervention in acute myocardial infarction: a pooled analysis from the STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study) trials. JACC Cardiovasc Interv
147. Dong-bao L, Qi H, Zhi L, et al. Predictors and long-term prognosis of angiographic slow/no-reflow phenomenon during emergency percutaneous coronary intervention for ST-elevated acute myocardial infarction. Clin Cardiol
148. Serruys PW, di Mario C, Piek J, et al. Prognostic value of intracoronary flow velocity and diameter stenosis in assessing the short- and long-term outcomes of coronary balloon angioplasty: the DEBATE Study (Doppler Endpoints Balloon Angioplasty Trial Europe). Circulation
149. Tsagalou EP, Anastasiou-Nana M, Agapitos E, et al. Depressed coronary flow reserve is associated with decreased myocardial capillary density in patients with heart failure due to idiopathic dilated cardiomyopathy. J Am Coll Cardiol
150. Kyriakidis MK, Dernellis JM, Androulakis AE, et al. Changes in phasic coronary blood flow velocity profile and relative coronary flow reserve in patients with hypertrophic obstructive cardiomyopathy. Circulation
151. Nishikawa S, Ito K, Adachi Y, et al. Ampulla (‘takotsubo’) cardiomyopathy of both ventricles: evaluation of microcirculation disturbance using 99 mTc-tetrofosmin myocardial single photon emission computed tomography and Doppler guide wire. Circ J
152. Chauhan A, Mullins PA, Taylor G, et al. Both endothelium-dependent and endothelium-independent function is impaired in patients with angina pectoris and normal coronary angiograms. Eur Heart J
153. Egashira K, Inou T, Hirooka Y, et al. Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms. N Engl J Med
154. Bugiardini R. Normal coronary arteries: clinical implications and further classification. Herz
155. Bugiardini R, Manfrini O, Pizzi C, et al. Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms. Circulation
156. Murakami H, Urabe K, Nishimura M. Inappropriate microvascular constriction produced transient ST-segment elevation in patients with syndrome X. J Am Coll Cardiol
157. Siebes M, Verhoeff BJ, Meuwissen M, et al. Single-wire pressure and flow velocity measurement to quantify coronary stenosis hemodynamics and effects of percutaneous interventions. Circulation
Keywords:© 2013 Italian Federation of Cardiology. All rights reserved.
cardiovascular magnetic resonance; coronary microcirculation; diagnostic investigation; intracoronary Doppler ultrasound; myocardial contrast echocardiography; PET; transthoracic Doppler echocardiography