Cardiovascular Research Advance Access originally published online on May 29, 2008
Cardiovascular Research 2008 80(2):165-174; doi:10.1093/cvr/cvn136
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A review of methods for assessment of coronary microvascular disease in both clinical and experimental settings
1 Department of Physiology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Arnimallee 22, D-14195 Berlin, Germany
2 Deutsches Herzzentrum Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany
3 Division of Cardiology, University of Perugia School of Medicine, Ospedale Silvestrini, 06156 Perugia, Italy
4 Department of Cardiology P, Kas Gentofte, 2900 Hellerup, Denmark
5 Cardiac and Vascular Sciences, St George’s, University of London, London SW17 0RE, UK
6 Med. Klinik IV, JWG-Universität Frankfurt, 60590 Frankfurt, Germany
7 Abt. Innere Medizin, Zentrum für Innere Medizin, Gießen, Germany
8 Division de Cardiologie, CHUV, 1011 Lausanne, Switzerland
9 Med. Klinik u. Poliklinik I, LMU München, Klinikum Großhadern, Munich, Germany
10 Institut für Physiologie, Universität zu Lübeck, Lübeck, Germany
11 Dipartimento di Medicina Interna, Policlinico S. Orsola, 40138 Bologna, Italy
* Corresponding author. Tel/fax: +39 051 347290. E-mail address: raffaele.bugiardini{at}unibo.it; rabugi{at}netscape.net
Received 7 January 2008; revised 20 May 2008; accepted 23 May 2008
Time for primary review: 23 days
 |
Abstract |
|---|
Top
Abstract
1. IntroductionObstructive disease of the large coronary arteries is the prominent cause for angina pectoris. However, angina may also occur in the absence of significant coronary atherosclerosis or coronary artery spasm, especially in women. Myocardial ischaemia in these patients is often associated with abnormalities of the coronary microcirculation and may thus represent a manifestation of coronary microvascular disease (CMD). Elucidation of the role of the microvasculature in the genesis of myocardial ischaemia and cardiac damage—in the presence or absence of obstructive coronary atherosclerosis—will certainly result in more rational diagnostic and therapeutic interventions for patients with ischaemic heart disease. Specifically targeted research based on improved assessment modalities is needed to improve the diagnosis of CMD and to translate current molecular, cellular, and physiological knowledge into new therapeutic options.
KEYWORDS Coronary microvascular disease; Microvascular angina; Plethysmography; Laser Doppler flux; Iontophoresis; Intravital microscopy
|
1. Introduction |
|---|
Ischaemic heart disease may frequently occur in the absence of significant coronary atherosclerosis, especially in women.1–3 Clinical reports suggest that in these patients, chest pain is related to coronary microvascular disease (CMD).4 CMD has been suggested to be present also in many other patients after relief of significant coronary atherosclerosis. Cardiologists are familiar with the phenomenon of slow myocardial blood flow in the setting of acute myocardial infarction5 or with the occurrence of persisting chest pain, and ischaemia, after percutaneous coronary intervention in the absence of residual stenosis in the culprit vessel.6
The implicit assumption in all of these patients is that reduced perfusion in the absence of significant stenosis would reflect impairment of the myocardial microcirculation. This assumption however needs confirmation.
It is the aim of the present article to briefly review the current knowledge on the involvement of CMD in different clinical scenarios and to define diagnostic approaches that are currently available or under development to assess CMD both invasively and non-invasively. This article has been prepared by members of the Working Group on Coronary Pathophysiology and Microcirculation of the European Society of Cardiology (ESC) and reflects their expertise and knowledge of this field.
|
2. Endothelial function/dysfunction |
|---|
Clinical symptoms of patients with non-obstructive coronary disease are often poorly understood. Chest pain could be explained by microvascular dysfunction. Abnormality of both endothelium-dependent and -independent vasodilatation may be a cause of vascular dysfunction, the most frequent cause being endothelial dysfunction.7–9
A normally functioning vascular endothelium is required for appropriate dilatation of arteries. Endothelial cells produce several mediators with vasorelaxing, anti-proliferative, anti-thrombotic, and anti-adherent effects, such as nitric oxide, prostacyclin, endothelium-derived hyperpolarizing factor, and C-type natriuretic peptide. These factors are balanced by the release of substances with opposing effects, such as endothelin, thromboxane A2, prostaglandin H2, and superoxide anion. Impairment of endothelium-dependent dilatation shifts a net dilator response to a variety of stimuli to a net constrictor response.
|
3. Coronary microvascular disease in different clinical scenarios |
|---|
There are three broad categories related to possible abnormalities of the coronary microcirculation. The first is referred to as the occurrence of ischaemic heart disease in the absence of angiographically significant coronary atherosclerosis and could result from inflammation and/or abnormal vasomotor regulation via endothelial-dependent and independent pathways.1–4 However, it should be considered that a normal or near-normal angiography does not necessarily rule out the presence of a large ‘hidden’ atherosclerotic burden.10,11 The second category refers to inadequate post-PCI and/or post-thrombolysis coronary reperfusion entailing an early phase referred to as ‘microvascular obstruction’12 possibly involving microembolic mechanisms, and a later phase of ‘microvascular dysfunction’, which may represent corollaries of reperfusion injury, including tissue oedema, neutrophil aggregation, and free-radical release.13,14 Finally, the third category is microvascular dysfunction in the context of epicardial vessel disease.
3.1 Acute coronary syndrome in the absence of significant coronary atherosclerosis
This phenomenon has been considered for many years as an angiographic curiosity. New data suggest that this is no longer appropriate. Patients with chest pain and normal or near-normal coronary angiograms belong to a group in which the prognosis is not necessarily as benign as previously reported2 especially if impaired endothelial function is diagnosed.15,16 Recent work revealed that the 1 year mortality rate of patients with acute coronary syndrome (ACS) but without obstructive coronary artery disease is high (1.0%), but these patients have a relatively lower incidence of death compared with patients with obstructive coronary artery disease in the same clinical setting (3.9%).17 The death rate in patients with chronic stable symptoms ranges from 0.6% per year in the absence of obstructive coronary lesions to 2.0% in the presence of such lesions.18,19 Patients with ACS are, therefore, usually at higher risk than patients with stable effort-related angina even in the absence of coronary obstructions. This demonstrates that we need more information on mechanisms underlying myocardial ischaemia and cardiac damage in patients presenting with an ACS and non-obstructive epicardial coronary disease. We also need reliable methods of risk stratification of patients with non-obstructive coronary disease.20
3.2 Chronic stable angina in patients with angiographically smooth normal coronary arteries
Recurrent chronic stable angina in patients with angiographically smooth coronary arteries and an abnormal stress test response has been referred to as ‘Cardiac Syndrome X’.1,21,22 In a subset of patients with Syndrome X, microvascular dysfunction can be demonstrated and this entity is commonly referred to as ‘microvascular angina’.23
Microcirculatory dysfunction has recently been associated with heart failure and/or diabetes and hypertension.4,5,24 Early-stage atherosclerosis is also associated with endothelial dysfunction and may contribute to microvascular dysfunction in less defined clinical subsets of patients.23,25,26 Finally, microvascular vasomotor dysfunction may occur independently of epicardial disease in heart transplant recipients, suggesting different entities of immune-mediated cardiac allograft vasculopathy,27 which may have prognostic importance for the deterioration of left ventricular function.28 A better understanding of the mechanisms of recurrent chronic angina in the absence of coronary disease at angiography should allow assigning an increasing fraction of these patients to distinct pathophysiological entities, which, in turn, may support the development of more specific treatment options.
3.3 Persistent/recurrent angina after successful revascularization
In many cases, percutaneous or surgical revascularization results in superior symptomatic relief of angina and improves exercise tolerance compared with medical therapy, but the benefits are seldom complete. It is common clinical experience to see that a substantial portion of patients still continues to experience symptoms under various circumstances. The long-term effects of PCI in comparison with an alternative path of continued medical treatment have been reviewed recently.6,29 At 5 years, 26% of patients in the PCI group and 28% of those in the medical therapy group showed persisting angina. Similar observations were reported in a multinational prospective study comparing the relative benefits of CABG and PCI in patients with multivessel disease potentially amenable to stent implantation.30 Although several mechanisms may be considered to explain the persistence of angina after a revascularization procedure (incomplete revascularization, graft/PTCA failure, and disease progression in native coronary arteries), the unexpected prevalence of angina after successful revascularization supports the hypothesis that persisting alterations of microcirculation contribute to the pathogenesis of ischaemia.31,32
3.4 No reflow
In patients with acute myocardial infarction, inadequate myocardial perfusion after successful coronary recanalization (no reflow) is associated with adverse cardiovascular events.33,34 No reflow may be associated with lack of patency or with loss of anatomic integrity of microvessels. The former is potentially reversible, whereas the latter is associated with definitive tissue damage.5
Multiple mechanisms may account for this finding. Necropsy studies have demonstrated the presence of thrombi in the coronary microvasculature from patients who died of acute myocardial infarction.35 Multiple mechanisms may account for this finding. Fibrinolysis generates elevated levels of free thrombin.35–37 The release of vasoactive mediators from activated thrombocytes may impair regional flow (microvascular spasm) and contribute to the no-reflow phenomenon.36,37 Oxygen free radicals generated soon after the release of the epicardial obstruction may inactivate nitric oxide, thus impairing endothelium-mediated vasodilatation, or directly cause microvascular spasm.38 Flow may also be impaired by adhesion of leukocytes to microvascular endothelium.39 Inadequate myocardial perfusion after successful coronary recanalization is associated with adverse cardiovascular events.33,34 No reflow may be associated with lack of patency or with loss of anatomic integrity of microvessels. The former is potentially reversible, whereas the latter is associated with definitive tissue damage.5 Although GP IIb/IIIa glycoprotein receptor inhibition generally ameliorates deficits in coronary flow reserve after acute myocardial infarction treated with primary PCI40 and improves prognosis in these patients, a potent therapeutic strategy to prevent or improve the no-reflow phenomenon is still missing.
3.5 Microvascular dysfunction in the context of epicardial vessel disease
Coronary artery stenosis decreases flow reserve in the vascular bed distally to a stenotic epicardial artery.41 Even early atherosclerotic lesions are associated with impaired endothelial coronary blood flow regulation.42 In addition to the effects of a stenosis on flow reserve within its own bed, coronary stenosis and occlusion also decrease flow reserve in adjacent non-stenotic beds in both experimental animal models and clinical populations.43 Importantly, global coronary flow reserve predicts cardiovascular events in patients with only minimal44 or intermediate epicardial lesions.45 It also predicts development of restenosis after coronary stent implantation.46 Blood flow-mediated shear stress on the endothelium of epicardial vessels controls the release of nitric oxide and other factors, regulating the vascular milieu and therefore may interfere with progression of atherosclerosis or restenosis development.47 The integrity of blood flow regulation in the microcirculation may thus have potential effects on the development of epicardial atherosclerosis.
|
4. Experimental assessment of coronary microcirculation |
|---|
Investigating alterations of microcirculatory function under a variety of pathophysiological conditions is a very active area of research, which has much contributed to our understanding of microcirculation. Many experimental models are available to investigate the coronary microcirculation; each has its own peculiarities, strengths, field of application, and limitations.
Rats, pigs, and dogs have been used most frequently as models in the study of intramyocardial circulation to validate imaging techniques, to examine postmortem pathology, to elucidate the pathophysiology of microvascular tone, and to study the effectiveness of pharmacological interventions in promoting microvascular dilation. Experimental models to study microvascular diameters and/or perfusion as well as cellular and molecular mechanisms include (i) in situ measurements; (ii) isolated heart preparations; (iii) isolated vessel approaches; (iv) cultured coronary microvascular endothelial and smooth muscle cells. Models for intravital microscopy of the beating heart in open-chest animals have been published more than 30 years ago.48,49 Later, microvascular diameter measurements by intravital microscopy in conjunction with luminal pressure determination have been performed to analyse the resistance distribution within the coronary microvasculature at rest and during dipyridamole-induced vasodilation.50 Also, different longitudinal gradients in the responsiveness of coronary arterioles to adenosine and nitroglycerin,51 and in alpha-1 and -2 receptor-mediated coronary constriction,52 have been identified. A needle-probe microscope53 allowed to identify differences between responses in epicardial vs. endocardial arterioles.54
4.1 In situ measurements
Perfusion in vivo may be measured invasively with intracoronary Doppler wires or with flow sensors positioned around the vessel in open-chest preparation or non-invasively with positron emission tomography (PET) and magnetic resonance imaging (MRI). Many of these techniques can also be applied to human subjects in contrast to the use of radioactive or colour-labelled microspheres, which remains the gold standard of regional myocardial blood flow assessment in the experimental setting. These methodologies have been employed to investigate a variety of issues, such as the loss of endothelial-dependent relaxation after ischaemia/reperfusion and the role of oxygen radicals,55 mechanisms of no-reflow phenomenon13,56 and of myocardial hibernation,57 and the impact of coronary risk factors on coronary flow reserve.58
4.2 Isolated heart preparations
Ex vivo isolated heart measurements of microvascular perfusion (rabbit, rat, guinea pig, and mouse) allow to accurately investigate intrinsic regulation of coronary blood flow in the absence of neuronal or hormonal influences without the confounding effects of changes in haemodynamics. Typical topics include the nitric oxide-dependent regulation of coronary blood flow59,60 and studies of the pathways of neutrophil/vessel wall61 and neutrophil/platelet/vessel wall62 interactions during post-ischaemic reperfusion. Arresting isolated rat hearts with tetrodotoxin also allows for microscopic investigation of microvascular diameter responses at constant metabolic demand.63
4.3 Isolated vessel approaches and cultured coronary microvascular cells
Assessment of diameter/tone responses in arterioles typically isolated by surgical excision of subcutaneous tissue is a very elegant, although technically demanding, method. It can be employed to test the reactivity profile of the microcirculation with respect to endothelin, arachidonic acid metabolites, catecholamines, and other vasoactive substances. This technique has also been used in humans to examine the endothelial function/dysfunction of large and small arteries essential hypertension.64,65 Recently, coronary vessels obtained from human atrial appendages removed during cardiopulmonary bypass were also studied.66 One step further, cultured coronary microvascular endothelial and smooth muscle cells allow to characterize vascular ion channels, which modulate vascular smooth muscle in microvessels, and to elucidate biochemical pathways by which endogenous vasoactive factors exert their influence.67,68
Regrettably, there are no animal models truly mimicking non-obstructive angina or CMD; in fact, to successfully develop such models, the underlying mechanisms need to be better known. At the moment, useful information can be gathered by investigating clinical conditions characterized by alteration of coronary artery reactivity in the absence of overt atherosclerothic stenosis.
|
5. Measuring myocardial microcirculatory perfusion in humans |
|---|
5.1 Non-invasive screening for abnormal vascular function in humans
Commonly used tests for screening for abnormal vasomotor regulation are single photon emission computed tomography (SPECT) stress myocardial perfusion imaging for patients who can exercise and dipyridamole or adenosine-induced vasodilation in conjunction with SPECT imaging or echocardiography for patients who cannot exercise.69–71 These techniques suffer from the limitation that only relative comparison of perfusion can be made, with no absolute estimates of blood flow. Additional methods are promising, including X-ray computed tomography (CT), echo Doppler, quantitative contrast echocardiography, and indicator-based techniques such as PET and MRI72–75 (Table 1). Such measurement of tissue perfusion, however, does not assess the microcirculation independently, in that these measures interrogate the flow resistance of both the epicardial artery and the microcirculation. In the presence of fixed or dynamic (vasomotor tone) epicardial stenoses, microvascular flow resistance cannot be directly estimated. However, some insights can be drawn. Indeed, if an intervention lowers computed resistance in a stenoic vascular bed but has no effect in the same patient in a non-stenotic bed, it would be reasonable to conclude that the decline in resistance observed in the stenotic bed reflects a change in epicardial rather than microvascular resistances. Conversely, if the non-stenotic vascular bed, but not the stenosis region, exhibits a decline in resistance, it would be logical to conclude that microvascular resistance in the stenostic zone was near minimal and that epicardial resistance was unchanged by the intervention.
|
|
6. Surrogate indexes for calculating coronary microvascular resistance |
|---|
There are some opportunities to develop surrogate indexes of microvascular flow resistance in the coronary arterial tree on the basis of invasively measured coronary flow parameters. These indexes are based on coronary flow parameters and hampered by the fact that myocardial flow has to be measured invasively.
6.1 Coronary and fractional flow reserve
Measuring the flow response to the downstream microvascular bed during the infusion of endothelium-dependent and endothelium-independent dilators into a coronary artery has been used to directly assess coronary microvascular function (Figure 1).16,76–78 A reduced coronary flow reserve in the context of a ‘normal’ intravascular ultrasound or normal fractional flow reserve indicates microcirculatory dysfunction.79 Current dual sensor pressure and flow wires allow relatively simple measurements of coronary flow reserve.80–82 This technique may provide further insight into coronary perfusion physiology via assessment of the flow pattern (e.g. diastolic deceleration time, systolic flow reversal) and allow to calculate indexes of absolute coronary blood flow and microcirculatory resistance (taking into account systemic haemodynamics and vessel size, derived by quantitative coronary angiography or intracoronary ultrasound).
|
6.2 Index of microvascular resistance
Distal coronary pressure multiplied by the hyperaemic mean transit time (which is inversely correlated to absolute flow, as measured simultaneously with the coronary pressure wire) may be used to roughly estimate microvascular resistance (index of microvascular resistance).83,84 Importantly, the pressure drop is a function of the square of flow across a coronary lesion and thus is geometrically not proportionally related. Changes in flow resistance of the vascular bed distal to the tip of the catheter can be detected. However, all resistance calculations based on this technique ignore very important physiological issues such as the true back pressure85 in the coronary circulation and coronary capacitance and so may not always provide an accurate estimate of the parameter of interest, namely microvascular tone. In addition, preliminary data show that blood flow values cannot be readily compared among different patients because the absolute resistance varies depending upon the tissue volume supplied by the respective artery.83
6.3 Thrombolysis in Myocardial Infarction Frame Count
The Corrected Thrombolysis In Myocardial Infarction (TIMI) Frame Count (CTFC) provides a simple index of coronary flow and myocardial perfusion. CTFC is an established method to provide a semiquantitative categorization of ‘epicardial’ blood flow, with the implicit assumption that slow flow in the absence of significant stenosis would reflect impairment of the myocardial ‘microcirculatory’ perfusion.86 CTFC has been used as measure of microvascular integrity and seems to predict outcome.87 Changes in CTFC not explained by concurrent changes in epicardial minimal lumen diameter (MLD) may be attributed to the resistance to flow at the level of coronary microcirculation. The concept of the CTFC/MLD ratio may thus be introduced as a composite measure of microvascular structure and function. Yet the value of this technique, too, needs to be fully elucidated. Measurements of blood flow using the TIMI frame count methodology require serial reproduction in patients not undergoing PCI or thrombolysis as a control group. These data are at present not available.
|
7. Peripheral indexes |
|---|
One alternative approach to invasive cardiac procedures enabling the assessment of alterations in microvascular function and structure is based on the assumption that microvascular alterations in peripheral tissues might reflect corresponding alterations in the heart. This has been confirmed for endothelial dysfunction in patients with systemic risk factors for atherosclerosis such as diabetes, hypercholesterolaemia, or hypertension88,89 and for patients with genetic alterations of microvascular responsiveness.90,91 However, only few studies have systematically assessed a direct correlation between peripheral and coronary vasodilator capacity, most of them limited by comparing different entities in the peripheral and coronary vasculature with respect to vessel size and agonist tested. It was shown that the peripheral perfusion response to transient forearm ischaemia (see also what follows for details) does not correlate with dipyridamole-induced myocardial hyperaemia.92 This might indicate different mechanisms of microvascular activation or regulation and advocate adequate care in respective extrapolations. However, peripheral techniques as summarized in what follows (Table 2) are less invasive and/or less expensive and time consuming compared with coronary catheterization or non-invasive screening strategies and may allow a more direct assessment of involved microvascular mechanisms.
|
7.1 Brachial artery post-ischaemic reflow
Brachial artery dilation in response to different stimuli can be measured with high-resolution ultrasound scanners. To test endothelium-dependent dilatation, flow changes are induced by forearm ischaemia followed by post-ischaemic hyperaemic reflow. In subjects with intact endothelial function, this typically results in a brachial artery diameter increase of
10%, and its exact quantification requires considerable technical skill and experience.93 Data obtained are then compared with the diameter response after sublingual application of glyceryl trinitrate, an endothelium-independent dilator. This technique is non-invasive, but it assesses endothelial function in a large conduit artery and not in microvessels. Nevertheless, the results seem to correlate with responses in skin microcirculation.94
7.2 Venous occlusion plethysmography
In order to assess microvascular endothelial function by venous occlusion plethysmography, the brachial artery is cannulated for the infusion of endothelium-dependent (e.g. acetylcholine) and -independent (e.g. Na-nitroprusside) vasodilators, rendering this technique moderately invasive. It has been successfully used to demonstrate the beneficial effects of statins95 or a third generation β-blocker96 on endothelial function in patients with hypercholesterolaemia and hypertension, respectively. Moreover, vasodilator capacity of the peripheral microcirculation assessed by venous occlusion plethysmography predicts cardiovascular events in patients with stable coronary artery disease97 or heart failure,98 as well as in ACS, with those patients at highest long-term risk in whom ACS-associated impairment of the microcirculation does not recover within the following weeks.99 Recently, finger plethysmography has been introduced, which provides further information on pulsatile flow patterns and allows the assessment of non-invasive stimuli (reactive hyperaemia).
7.3 Laser Doppler fluxmetry
Laser Doppler fluxmetry (LDF) is becoming increasingly popular for the estimation of skin microvascular blood flow.100 The surface investigated is illuminated with a laser spot. The frequency of the laser light is altered by multiple reflections at flowing red blood cells. The resulting frequency shift in light reflected from the tissue is proportional to the product of red cell number and flow velocity (equal to a flux) in the sample region, which is usually a half sphere with a diameter of 1 mm. Since the local perfusion in the skin is very heterogeneous, it is helpful to assess larger areas of the tissue surface by two-dimensional scanning LDF imaging. Additional information on microvascular function may be obtained by spectral analysis of the laser Doppler flux time series using wavelet transforms. Oscillations in skin perfusion with frequencies around 0.1 and 0.01 Hz are considered to reflect myogenic and endothelial activities, respectively.101
In combination with local drug application by iontophoresis, the LDF technique allows for non-invasive study of microvascular responses to a variety of pharmacological stimuli. Iontophoresis relies on drug molecules carrying a positive or negative charge which migrate across the skin when a respective potential is applied, in direct proportion to the current applied. Thus minute quantities of a vasoactive drug can be administered to the microvasculature under investigation in a controlled fashion, without causing systemic effects. Acetylcholine and Na-nitroprusside are typical substances to assess endothelium-dependent and -independent vasodilator responses.102,103 In contrast to the techniques discussed earlier, this method also allows for the application of vasoconstrictors. Alpha-adrenergic vasoregulation has been analysed using iontophoretic delivery of tyramine, phentolamine, bretylium, and norepinephrine.103 Interestingly, iontophoretically delivered urotensin II may induce vasodilation in the skin microvasculature of healthy control subjects but constriction in patients with chronic heart failure.104
Thus, iontophoresis in conjunction with laser Doppler flowmetry or imaging seems most attractive for detailed study of peripheral microvascular function because it is not only completely non-invasive but also allows for the assessment of endothelium-dependent and -independent vasodilator reserve and of vasoconstrictor sensitivity. Figure 2 shows an example of laser Doppler flux tracings of skin perfusion in a patient with Parvovirus B19-induced cardiomyopathy.
|
7.4 Clinical intravital microscopy
In addition to functional deficits, apparent microvascular dysfunction may also be due to structural alterations of the microvasculature such as rarefaction and/or remodelling.105,106 Evaluation of microvascular density requires direct visualization of microvascular networks by clinical intravital microscopy, which is possible only in select tissues. Capillaroscopy of the nailfold or oral tissues (gingival, sublingual, or buccal mucosa) allows to study capillary morphology, capillary density, and capillary blood velocity.107–109 The introduction of new clinical intravital microscopes (e.g. orthogonal polarization spectral imaging) has improved image quality and ease of application and renders additional tissues such as sublingual or buccal mucosa accessible.110 Specific image analysis approaches additionally allow the measurement of arteriolar or venular blood flow velocity111 and pulsatility.112
Arteriolar morphology can also be analysed by retinography.89 Focal or generalized luminal narrowing, as well as arteriovenous nicking, i.e. the indentation and displacement of venules by crossing arterioles owing to structural changes in the arteriolar wall, has been associated with hypertension,113 metabolic syndrome,114 coronary heart disease,115 and stroke.116 The major disadvantage of using retinography for the analysis of arteriolar remodelling is the qualitative nature of the results. A common problem of all intravital microscopy approaches lies in the difficulty of extracting quantitative data from the images, which usually requires time consuming off-line analysis of digitized video sequences.
7.5 Subcutaneous biopsy
In order to obtain quantitative data on arteriolar wall thickness to lumen ratio, histological analysis of tissue from biopsies is indispensable. In contrast to cardiac tissue, subcutaneous fat or gluteal muscle specimens can be collected in sufficient quantities with little discomfort to the patients.117 To support the assumption that microvascular alterations occur not only in the heart or the brain but in all tissues throughout the body, results obtained in these specimens can be compared with retinography findings and with functional data obtained in the coronary and in peripheral circulations. The same specimens may also be used to investigate the mechanisms responsible for the observed morphological alterations.118
|
8. Perspectives |
|---|
Although many studies have supported the role of CMD in explaining chest pain symptoms in a variety of clinical settings, convincing evidence of a causal relationship between myocardial ischaemia and CMD and of its pathophysiological mechanisms is sparse. We therefore strongly emphasize that investigations designed to elucidate the regulation of the coronary microcirculation in health and disease should incorporate the best technological advances in molecular biology, biochemistry, imaging, and physiological measurements.
Future research needs to encompass both basic and clinical investigations and to compare peripheral investigations of microcirculation with parallel measurements in the heart. Development and testing of new and improved diagnostic procedures for CMD are needed as well. Currently, the coronary microcirculation moves into the focus of new therapeutic strategies of cardiac disease driven by recent insights into, e.g. endothelial effects of drugs such as statins or ACE-inhibitors, or the restorative function of endothelial progenitor cells119,120 and haematopoietic stem/progenitor cells. Established and experimental therapies for the prevention and treatment of microvascular dysfunction should be tested in animal and cell-based models. In addition, clinically oriented investigations will be indispensable to understand the role of the coronary microcirculation in cardiac disease and to gain more precise insights into the relationships between coronary microvascular dysfunction, inducible myocardial ischaemia, and adverse outcome. Areas such as genetic predisposition to microvascular disease in response to hypertension and/or other cardiovascular risk factors also deserve emphasis.
|
9. Conclusions |
|---|
The authors perceive that there is an impressive lack of clinical and pathophysiological information on the role of CMD in cardiac disease. This is in part due to the gap between current experimental studies of the coronary microcirculation and clinical investigations in this area. Increased collaboration between basic science and clinical-oriented researchers should help bridging this gap and help develop improved experimental and clinical approaches to assess and treat CMD.
Conflict of interest: none declared.
|
Funding |
|---|
None.
|
References |
|---|
- Kaski JC. Pathophysiology and management of patients with chest pain and normal coronary arteriograms (cardiac syndrome X). Circulation (2004) 109:568–572.
[Free Full Text] - Bugiardini R, Bairey Merz CN. Angina with ‘normal’ coronary arteries: a changing philosophy. JAMA (2005) 293:477–484.
[Abstract/Free Full Text] - Lanza GA. Cardiac syndrome X: a critical overview and future perspectives. Heart (2007) 93:159–166.
[Abstract/Free Full Text] - Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med (2007) 356:830–840.
[Free Full Text] - Galiuto L, Gabrielli FA, Lombardo A, La TG, Scara A, Rebuzzi AG, et al. Reversible microvascular dysfunction coupled with persistent myocardial dysfunction: implications for post-infarct left ventricular remodeling. Heart (2006) 93:565–571.[CrossRef][Web of Science][Medline]
- Poole-Wilson PA, Pocock SJ, Fox KA, Henderson RA, Wheatley DJ, Chamberlain DA, et al. Interventional versus conservative treatment in acute non-ST elevation coronary syndrome: time course of patient management and disease events over one year in the RITA 3 trial. Heart (2006) 92:1473–1479.
[Abstract/Free Full Text] - Gould KL, Martucci JP, Goldberg DI, Hess MJ, Edens RP, Latifi R, 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. A potential noninvasive marker of healing coronary endothelium. Circulation (1994) 89:1530–1538.
[Abstract/Free Full Text] - Chen JW, Hsu NW, Wu TC, Lin SJ, Chang MS. Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X. Am J Cardiol (2002) 90:974–982.[CrossRef][Web of Science][Medline]
- Gielen S, Schuler G, Hambrecht R. Exercise training in coronary artery disease and coronary vasomotion. Circulation (2001) 103:E1–E6.[Web of Science][Medline]
- Tuzcu EM, Kapadia SR, Tutar E, Ziada KM, Hobbs RE, McCarthy PM, et al. High prevalence of coronary atherosclerosis in asymptomatic teenagers and young adults: evidence from intravascular ultrasound. Circulation (2001) 103:2705–2710.
[Abstract/Free Full Text] - Jeremias A, Ge J, Erbel R. New insight into plaque healing after plaque rupture with subsequent thrombus formation detected by intravascular ultrasound. Heart (1997) 77:293.
[Free Full Text] - Erbel R, Heusch G. Coronary microembolization. J Am Coll Cardiol (2000) 36:22–24.
[Free Full Text] - Ambrosio G, Weisman HF, Mannisi JA, Becker LC. Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow. Circulation (1989) 80:1846–1861.
[Abstract/Free Full Text] - Duilio C, Ambrosio G, Kuppusamy P, DiPaula A, Becker LC, Zweier JL. Neutrophils are primary source of O2 radicals during reperfusion after prolonged myocardial ischemia. Am J Physiol Heart Circ Physiol (2001) 280:H2649–H2657.
[Abstract/Free Full Text] - Herrmann J, Lerman A. The endothelium: dysfunction and beyond. J Nucl Cardiol (2001) 8:197–206.[CrossRef][Web of Science][Medline]
- Bugiardini R, Manfrini O, Pizzi C, Fontana F, Morgagni G. Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms. Circulation (2004) 109:2518–2523.
[Abstract/Free Full Text] - 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 (2006) 166:1391–1395.
[Abstract/Free Full Text] - Johnson BD, Shaw LJ, Pepine CJ, Reis SE, Kelsey SF, Sopko G, et al. Persistent chest pain predicts cardiovascular events in women without obstructive coronary artery disease: results from the NIH-NHLBI-sponsored Women’s Ischaemia Syndrome Evaluation (WISE) study. Eur Heart J (2006) 27:1408–1415.
[Abstract/Free Full Text] - Daly C, Clemens F, Lopez Sendon JL, Tavazzi L, Boersma E, Danchin N, et al. Gender differences in the management and clinical outcome of stable angina. Circulation (2006) 113:490–498.
[Abstract/Free Full Text] - Bugiardini R, Badimon L, Collins P, Erbel R, Fox K, Hamm C, et al. Angina ‘normal’ coronary angiography vascular dysfunction: risk assessment strategies. PLoS Med (2007) 4:e12.[CrossRef][Medline]
- Kemp HG Jr. Left ventricular function in patients with the anginal syndrome and normal coronary arteriograms. Am J Cardiol (1973) 32:375–376.[CrossRef][Web of Science][Medline]
- Kaski JC, Crea F, Nihoyannopoulos P, Hackett D, Maseri A. Transient myocardial ischemia during daily life in patients with syndrome X. Am J Cardiol (1986) 58:1242–1247.[CrossRef][Web of Science][Medline]
- Thorne S, Mullen MJ, Clarkson P, Donald AE, Deanfield JE. Early endothelial dysfunction in adults at risk from atherosclerosis: different responses to L-arginine. J Am Coll Cardiol (1998) 32:110–116.
[Abstract/Free Full Text] - Levy BI, Ambrosio G, Pries AR, Struijker-Boudier HA. Microcirculation in hypertension: a new target for treatment? Circulation (2001) 104:735–740.
[Free Full Text] - Lerman A, Holmes DR Jr, Bell MR, Garratt KN, Nishimura RA, Burnett JC Jr. Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans. Circulation (1995) 92:2426–2431.
[Abstract/Free Full Text] - Zeiher AM, Drexler H, Wollschlager H, Just H. Endothelial dysfunction of the coronary microvasculature is associated with coronary blood flow regulation in patients with early atherosclerosis. Circulation (1991) 84:1984–1992.
[Abstract/Free Full Text] - Weis M, von SW. Coronary artery disease in the transplanted heart. Annu Rev Med (2000) 51:81–100.[CrossRef][Web of Science][Medline]
- Weis M, Hartmann A, Olbrich HG, Griher AM. Prognostic significance of coronary flow reserve on left ventricular ejection fraction in cardiac transplant recipients. Transplantation (1998) 65:103–108.[Web of Science][Medline]
- Fox KA, Poole-Wilson P, Clayton TC, Henderson RA, Shaw TR, Wheatley DJ, et al. 5-year outcome of an interventional strategy in non-ST-elevation acute coronary syndrome: the British Heart Foundation RITA 3 randomised trial. Lancet (2005) 366:914–920.[CrossRef][Web of Science][Medline]
- Legrand VM, Serruys PW, Unger F, van Hout BA, Vrolix MC, Fransen GM, et al. Three-year outcome after coronary stenting versus bypass surgery for the treatment of multivessel disease. Circulation (2004) 109:1114–1120.
[Abstract/Free Full Text] - Marzilli M, Sambuceti G, Fedele S, L’Abbate A. Coronary microcirculatory vasoconstriction during ischemia in patients with unstable angina. J Am Coll Cardiol (2000) 35:327–334.
[Abstract/Free Full Text] - Sambuceti G, Marzilli M, Fedele S, Marini C, L’Abbate A. Paradoxical increase in microvascular resistance during tachycardia downstream from a severe stenosis in patients with coronary artery disease: reversal by angioplasty. Circulation (2001) 103:2352–2360.
[Abstract/Free Full Text] - Glazier JJ. Attenuation of reperfusion microvascular ischemia by aqueous oxygen: experimental and clinical observations. Am Heart J (2005) 149:580–584.[CrossRef][Web of Science][Medline]
- Peterson ED, Shaw LJ, Califf RM. Risk stratification after myocardial infarction. Ann Intern Med (1997) 126:561–582.
[Abstract/Free Full Text] - Kaul S, Ito H. Microvasculature in acute myocardial ischemia: part II: evolving concepts in pathophysiology, diagnosis, and treatment. Circulation (2004) 109:310–315.
[Free Full Text] - Hirsh PD, Hillis LD, Campbell WB, Firth BG, Willerson JT. Release of prostaglandins and thromboxane into the coronary circulation in patients with ischemic heart disease. N Engl J Med (1981) 304:685–691.[Abstract]
- Rucker M, Schafer T, Roesken F, Spitzer WJ, Bauer M, Menger MD. Local heat-shock priming-induced improvement in microvascular perfusion in osteomyocutaneous flaps is mediated by heat-shock protein 32. Br J Surg (2001) 88:450–457.[CrossRef][Web of Science][Medline]
- Sun H, Mohri M, Shimokawa H, Usui M, Urakami L, Takeshita A. Coronary microvascular spasm causes myocardial ischemia in patients with vasospastic angina. J Am Coll Cardiol (2002) 39:847–851.
[Abstract/Free Full Text] - Christiansen JP, Leong-Poi H, Klibanov AL, Kaul S, Lindner JR. Noninvasive imaging of myocardial reperfusion injury using leukocyte-targeted contrast echocardiography. Circulation (2002) 105:1764–1767.
[Abstract/Free Full Text] - Neumann FJ, Blasini R, Schmitt C, Alt E, Dirschinger J, Gawaz M, et al. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation (1998) 98:2695–2701.
[Abstract/Free Full Text] - Zeiher AM, Drexler H, Wollschlager H, Just H. Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation (1991) 83:391–401.
[Abstract/Free Full Text] - Schachinger V, Britten MB, Elsner M, Walter DH, Scharrer I, Zeiher AM. A positive family history of premature coronary artery disease is associated with impaired endothelium-dependent coronary blood flow regulation. Circulation (1999) 100:1502–1508.
[Abstract/Free Full Text] - Sambuceti G, Marzullo P, Giorgetti A, Neglia D, Marzilli M, Salvadori P, et al. Global alteration in perfusion response to increasing oxygen consumption in patients with single-vessel coronary artery disease. Circulation (1994) 90:1696–1705.
[Abstract/Free Full Text] - Britten MB, Zeiher AM, Schachinger V. Microvascular dysfunction in angiographically normal or mildly diseased coronary arteries predicts adverse cardiovascular long-term outcome. Coron Artery Dis (2004) 15:259–264.[CrossRef][Web of Science][Medline]
- Chamuleau SA, Tio RA, de Cock CC, de Muinck ED, Pijls NH, van Eck-Smit BL, et al. Prognostic value of coronary blood flow velocity and myocardial perfusion in intermediate coronary narrowings and multivessel disease. J Am Coll Cardiol (2002) 39:852–858.
[Abstract/Free Full Text] - Haude M, Baumgart D, Verna E, Piek JJ, Vrints C, Probst P, et al. Intracoronary Doppler- and quantitative coronary angiography-derived predictors of major adverse cardiac events after stent implantation. Circulation (2001) 103:1212–1217.
[Abstract/Free Full Text] - Cooke JP, Tsao PS. Go with the flow. Circulation (2001) 103:2773–2775.
[Free Full Text] - Steinhausen M, Tillmanns H, Thederan H. Microcirculation of the epicardial layer of the heart. Pflugers Arch (1978) 378:9–14.[CrossRef][Web of Science][Medline]
- Tillmanns H, Ikeda S, Hansen H, Sarma JSM, Fauvel J-M, Bing RJ. Microcirculation in the ventricle of the dog and turtle. Mol Cell (1974) 34:561–569.
- Chilian WM, Layne SM, Klausner EC, Eastham D, Marcus ML. Redistribution of coronary microvascular resistance produced by dipyridamole. Am J Physiol (1989) 256:H383–H390.[Web of Science][Medline]
- Habazettl H, Vollmar B, Christ M, Baier H, Conzen PF, Peter K. Heterogeneous microvascular coronary vasodilation by adenosine and nitroglycerin in dogs. J Appl Physiol (1994) 76:1951–1960.
[Abstract/Free Full Text] - Chilian WM. Functional distribution of alpha 1- and alpha 2-adrenergic receptors in the coronary microcirculation. Circulation (1991) 84:2108–2122.
[Abstract/Free Full Text] - Yada T, Hiramatsu O, Kimura A, Goto M, Ogasawara Y, Tsujioka K, et al. In vivo observation of subendocardial microvessels of the beating porcine heart using a needle-probe videomicroscope with a CCD camera. Mol Cell (1993) 72:939–946.
- Merkus D, Vergroesen I, Hiramatsu O, Tachibana H, Nakamoto H, Toyota E, et al. Stenosis differentially affects subendocardial and subepicardial arterioles in vivo. Am J Physiol Heart Circ Physiol (2001) 280:H1674–H1682.
[Abstract/Free Full Text] - Mehta JL, Nichols WW, Donnelly WH, Lawson DL, Saldeen TG. Impaired canine coronary vasodilator response to acetylcholine and bradykinin after occlusion-reperfusion. Circ Res (1989) 64:43–54.
[Abstract/Free Full Text] - Golino P, Ragni M, Cirillo P, Avvedimento VE, Feliciello A, Esposito N, et al. Effects of tissue factor induced by oxygen free radicals on coronary flow during reperfusion. Nat Med (1996) 2:35–40.[CrossRef][Web of Science][Medline]
- Kim SJ, Peppas A, Hong SK, Yang G, Huang Y, Diaz G, et al. Persistent stunning induces myocardial hibernation and protection: flow/function and metabolic mechanisms. Circ Res (2003) 92:1233–1239.
[Abstract/Free Full Text] - Rosen BD, Lima JA, Nasir K, Edvardsen T, Folsom AR, Lai S, et al. Lower myocardial perfusion reserve is associated with decreased regional left ventricular function in asymptomatic participants of the multi-ethnic study of atherosclerosis. Circulation (2006) 114:289–297.
[Abstract/Free Full Text] - Giraldez RR, Panda A, Xia Y, Sanders SP, Zweier JL. Decreased nitric-oxide synthase activity causes impaired endothelium-dependent relaxation in the postischemic heart. J Biol Chem (1997) 272:21420–21426.
[Abstract/Free Full Text] - Paolocci N, Biondi R, Bettini M, Lee CI, Berlowitz CO, Rossi R, et al. Oxygen radical-mediated reduction in basal and agonist-evoked NO release in isolated rat heart. J Mol Cell Cardiol (2001) 33:671–679.[CrossRef][Web of Science][Medline]
- Tritto I, Wang P, Kuppusamy P, Giraldez R, Zweier JL, Ambrosio G. The anti-anginal drug trimetazidine reduces neutrophil-mediated cardiac reperfusion injury. J Cardiovasc Pharmacol (2005) 46:89–98.[CrossRef][Web of Science][Medline]
- Kupatt C, Habazettl H, Hanusch P, Wichels R, Hahnel D, Becker BF, et al. c7E3Fab reduces postischemic leukocyte–thrombocyte interaction mediated by fibrinogen. Implications for myocardial reperfusion injury. Arterioscler Thromb Vasc Biol (2000) 20:2226–2232.
[Abstract/Free Full Text] - Goebel S, Kuebler WM, Cornelissen AJM, Kuppe H, Pries AR, Habazettl H. In situ analysis of coronary terminal arteriole diameter responses: technical report of a new experimental model. J Vasc Res (2003) 40:442–448.[CrossRef][Web of Science][Medline]
- Park JB, Charbonneau F, Schiffrin EL. Correlation of endothelial function in large and small arteries in human essential hypertension. J Hypertens (2001) 19:415–420.[CrossRef][Web of Science][Medline]
- Schiffrin EL, Park JB, Intengan HD, Touyz RM. Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan. Circulation (2000) 101:1653–1659.
[Abstract/Free Full Text] - Sato A, Terata K, Miura H, Toyama K, Loberiza FR Jr, Hatoum OA, et al. Mechanism of vasodilation to adenosine in coronary arterioles from patients with heart disease. Am J Physiol Heart Circ Physiol (2005) 288:H1633–H1640.
[Abstract/Free Full Text] - Li JM, Mullen AM, Yun S, Wientjes F, Brouns GY, Thrasher AJ, et al. Essential role of the NADPH oxidase subunit p47(phox) in endothelial cell superoxide production in response to phorbol ester and tumor necrosis factor-alpha. Circ Res (2002) 90:143–150.
[Abstract/Free Full Text] - Liu Y, Terata K, Rusch NJ, Gutterman DD. High glucose impairs voltage-gated K(+) channel current in rat small coronary arteries. Circ Res (2001) 89:146–152.
[Abstract/Free Full Text] - Hachamovitch R, Berman DS, Kiat H, Cohen I, Friedman JD, Shaw LJ. Value of stress myocardial perfusion single photon emission computed tomography in patients with normal resting electrocardiograms: an evaluation of incremental prognostic value and cost-effectiveness. Circulation (2002) 105:823–829.
[Abstract/Free Full Text] - Bartel T, Yang Y, Muller S, Wenzel RR, Baumgart D, Philipp T, et al. Noninvasive assessment of microvascular function in arterial hypertension by transthoracic Doppler harmonic echocardiography. J Am Coll Cardiol (2002) 39:2012–2018.
[Abstract/Free Full Text] - Poelaert JI, Schupfer G. Hemodynamic monitoring utilizing transesophageal echocardiography: the relationships among pressure, flow, and function. Chest (2005) 127:379–390.[CrossRef][Web of Science][Medline]
- Huggins GS, Pasternak RC, Alpert NM, Fischman AJ, Gewirtz H. Effects of short-term treatment of hyperlipidemia on coronary vasodilator function and myocardial perfusion in regions having substantial impairment of baseline dilator reverse. Circulation (1998) 98:1291–1296.
[Abstract/Free Full Text] - Panting JR, Gatehouse PD, Yang GZ, Grothues F, Firmin DN, Collins P, et al. Abnormal subendocardial perfusion in cardiac syndrome X detected by cardiovascular magnetic resonance imaging. N Engl J Med (2002) 346:1948–1953.
[Abstract/Free Full Text] - Doyle M, Fuisz A, Kortright E, Biederman RW, Walsh EG, Martin ET, et al. The impact of myocardial flow reserve on the detection of coronary artery disease by perfusion imaging methods: an NHLBI WISE study. J Cardiovasc Magn Reson (2003) 5:475–485.[CrossRef][Web of Science][Medline]
- Wagner B, Anton M, Nekolla SG, Reder S, Henke J, Seidl S, et al. Noninvasive characterization of myocardial molecular interventions by integrated positron emission tomography and computed tomography. J Am Coll Cardiol (2006) 48:2107–2115.
[Abstract/Free Full Text] - Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation (2000) 101:948–954.
[Abstract/Free Full Text] - Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation (2000) 101:1899–1906.
[Abstract/Free Full Text] - Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation (2002) 106:653–658.
[Abstract/Free Full Text] - Fearon WF, Nakamura M, Lee DP, Rezaee M, Vagelos RH, Hunt SA, et al. Simultaneous assessment of fractional and coronary flow reserves in cardiac transplant recipients: Physiologic Investigation for Transplant Arteriopathy (PITA Study). Circulation (2003) 108:1605–1610.
[Abstract/Free Full Text] - Baumgart D, Haude M, Liu F, Ge J, Goerge G, Erbel R. Current concepts of coronary flow reserve for clinical decision making during cardiac catheterization. Am Heart J (1998) 136:136–149.[CrossRef][Web of Science][Medline]
- Kern MJ. Coronary physiology revisited: practical insights from the cardiac catheterization laboratory. Circulation (2000) 101:1344–1351.
[Abstract/Free Full Text] - Siebes M, Verhoeff BJ, Meuwissen M, de Winter RJ, Spaan JA, Piek JJ. Single-wire pressure and flow velocity measurement to quantify coronary stenosis hemodynamics and effects of percutaneous interventions. Circulation (2004) 109:756–762.
[Abstract/Free Full Text] - Kern MJ, Lerman A, Bech JW, De BB, Eeckhout E, Fearon WF, et al. Physiological assessment of coronary artery disease in the cardiac catheterization laboratory: a scientific statement from the American Heart Association Committee on Diagnostic and Interventional Cardiac Catheterization, Council on Clinical Cardiology. Circulation (2006) 114:1321–1341.
[Abstract/Free Full Text] - Fearon WF, Balsam LB, Farouque HM, Caffarelli AD, Robbins RC, Fitzgerald PJ, et al. Novel index for invasively assessing the coronary microcirculation. Circulation (2003) 107:3129–3132.
[Abstract/Free Full Text] - Feigl EO. Coronary physiology. Physiol Rev (1983) 63:1–205.
[Abstract/Free Full Text] - Gibson CM, Cannon CP, Daley WL, Dodge JT Jr, Alexander B Jr, Marble SJ, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation (1996) 93:879–888.
[Abstract/Free Full Text] - Gibson CM, Morrow DA, Murphy SA, Palabrica TM, Jennings LK, Stone PH, et al. A randomized trial to evaluate the relative protection against post-percutaneous coronary intervention microvascular dysfunction, ischemia, and inflammation among antiplatelet and antithrombotic agents: the PROTECT-TIMI-30 trial. J Am Coll Cardiol (2006) 47:2364–2373.
[Abstract/Free Full Text] - Kuvin JT, Karas RH. Clinical utility of endothelial function testing: ready for prime time? Circulation (2003) 107:3243–3247.
[Free Full Text] - Alam TA, Seifalian AM, Baker D. A review of methods currently used for assessment of in vivo endothelial function. Eur J Vasc Endovasc Surg (2005) 29:269–276.[CrossRef][Web of Science][Medline]
- Gratze G, Fortin J, Labugger R, Binder A, Kotanko P, Timmermann B, et al. Beta-2 adrenergic receptor variants affect resting blood pressure and agonist-induced vasodilation in young adult Caucasians. Hypertension (1999) 33:1425–1430.
[Abstract/Free Full Text] - Park JS, Zhang SY, Jo SH, Seo JB, Li L, Park KW, et al. Common adrenergic receptor polymorphisms as novel risk factors for vasospastic angina. Am Heart J (2006) 151:864–869.[CrossRef][Web of Science][Medline]
- Bottcher M, Madsen MM, Refsgaard J, Buus NH, Dorup I, Nielsen TT, et al. Peripheral flow response to transient arterial forearm occlusion does not reflect myocardial perfusion reserve. Circulation (2001) 103:1109–1114.
[Abstract/Free Full Text] - Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol (2002) 39:257–265.
[Abstract/Free Full Text] - Hansell J, Henareh L, Agewall S, Norman M. Non-invasive assessment of endothelial function—relation between vasodilatory responses in skin microcirculation and brachial artery. Clin Physiol Funct Imaging (2004) 24:317–322.[CrossRef][Web of Science][Medline]
- O’Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation (1997) 95:1126–1131.
[Abstract/Free Full Text] - Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study. Circulation (2001) 104:511–514.
[Abstract/Free Full Text] - Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation (2001) 104:2673–2678.
[Abstract/Free Full Text] - Heitzer T, Baldus S, von KY, Rudolph V, Meinertz T. Systemic endothelial dysfunction as an early predictor of adverse outcome in heart failure. Arterioscler Thromb Vasc Biol (2005) 25:1174–1179.
[Abstract/Free Full Text] - Fichtlscherer S, Breuer S, Zeiher AM. Prognostic value of systemic endothelial dysfunction in patients with acute coronary syndromes: further evidence for the existence of the ‘vulnerable’ patient. Circulation (2004) 110:1926–1932.
[Abstract/Free Full Text] - Kubli S, Waeber B, Dalle-Ave A, Feihl F. Reproducibility of laser Doppler imaging of skin blood flow as a tool to assess endothelial function. J Cardiovasc Pharmacol (2000) 36:640–648.[CrossRef][Web of Science][Medline]
- Kvandal P, Stefanovska A, Veber M, Kvernmo HD, Kirkeboen KA. Regulation of human cutaneous circulation evaluated by laser Doppler flowmetry, iontophoresis, and spectral analysis: importance of nitric oxide and prostaglandines. Microvasc Res (2003) 65:160–171.[CrossRef][Web of Science][Medline]
- Serne EH, Stehouwer CD, ter Maaten JC, ter Wee PM, Rauwerda JA, Donker AJ, et al. Microvascular function relates to insulin sensitivity and blood pressure in normal subjects. Circulation (1999) 99:896–902.
[Abstract/Free Full Text] - Medow MS, Minson CT, Stewart JM. Decreased microvascular nitric oxide-dependent vasodilation in postural tachycardia syndrome. Circulation (2005) 112:2611–2618.
[Abstract/Free Full Text] - Lim M, Honisett S, Sparkes CD, Komesaroff P, Kompa A, Krum H. Differential effect of urotensin II on vascular tone in normal subjects and patients with chronic heart failure. Circulation (2004) 109:1212–1214.
[Abstract/Free Full Text] - Pries AR, Secomb TW, Gaehtgens P. Design principles of vascular beds. Circ Res (1995) 77:1017–1023.
[Abstract/Free Full Text] - Zakrzewicz A, Secomb TW, Pries AR. Angioadaptation: keeping the vascular system in shape. News Physiol Sci (2002) 17:197–201.
[Abstract/Free Full Text] - Yvonne-Tee GB, Rasool AH, Halim AS, Rahman AR. Noninvasive assessment of cutaneous vascular function in vivo using capillaroscopy, plethysmography and laser-Doppler instruments: its strengths and weaknesses. Clin Hemorheol Microcirc (2006) 34:457–473.[Web of Science][Medline]
- Hern S, Mortimer PS. Visualization of dermal blood vessels—capillaroscopy. Clin Exp Dermatol (1999) 24:473–478.[CrossRef][Web of Science][Medline]
- Scardina GA, Messina P. Morphologic changes in the microcirculation induced by chronic smoking habit: a videocapillaroscopic study on the human gingival mucosa. Am J Dent (2005) 18:301–304.[Web of Science][Medline]
- Groner W, Winkelman JW, Harris AG, Ince C, Bouma GJ, Messmer K, et al. Orthogonal polarization spectral imaging: a new method for study of the microcirculation. Nat Med (1999) 5:1209–1212.[CrossRef][Web of Science][Medline]
- Lindert J, Werner J, Redlin M, Kuppe H, Habazettl H, Pries AR. OPS imaging of human microcirculation: a short technical report. J Vasc Res (2002) 39:368–372.[CrossRef][Web of Science][Medline]
- Habazettl H, Kukucka M, Weng YG, Kuebler WM, Hetzer R, Kuppe H, et al. Arteriolar blood flow pulsatility in a patient before and after implantation of an axial flow pump. Ann Thorac Surg (2006) 81:1109–1111.
[Abstract/Free Full Text] - Cuspidi C, Meani S, Salerno M, Fusi V, Severgnini B, Valerio C, et al. Retinal microvascular changes and target organ damage in untreated essential hypertensives. J Hypertens (2004) 22:2095–2102.[CrossRef][Web of Science][Medline]
- Mule G, Nardi E, Cottone S, Cusimano P, Volpe V, Piazza G, et al. Influence of metabolic syndrome on hypertension-related target organ damage. J Intern Med (2005) 257:503–513.[CrossRef][Web of Science][Medline]
- Wong TY, Klein R, Sharrett AR, Duncan BB, Couper DJ, Tielsch JM, et al. Retinal arteriolar narrowing and risk of coronary heart disease in men and women. The Atherosclerosis Risk in Communities Study. JAMA (2002) 287:1153–1159.
[Abstract/Free Full Text] - Wong TY, Klein R, Couper DJ, Cooper LS, Shahar E, Hubbard LD, et al. Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study. Lancet (2001) 358:1134–1140.[CrossRef][Web of Science][Medline]
- Rizzoni D, Muiesan ML, Porteri E, Salvetti M, Castellano M, Bettoni G, et al. Relations between cardiac and vascular structure in patients with primary and secondary hypertension. J Am Coll Cardiol (1998) 32:985–992.
[Abstract/Free Full Text] - Rizzoni D, Agabiti RE. Small artery remodeling in hypertension and diabetes. Curr Hypertens Rep (2006) 8:90–95.[CrossRef][Web of Science][Medline]
- Erbs S, Linke A, Adams V, Lenk K, Thiele H, Diederich KW, et al. Transplantation of blood-derived progenitor cells after recanalization of chronic coronary artery occlusion: first randomized and placebo-controlled study. Circ Res (2005) 97:756–762.
[Abstract/Free Full Text] - Schachinger V, Assmus B, Honold J, Lehmann R, Hofmann WK, Martin H, et al. Normalization of coronary blood flow in the infarct-related artery after intracoronary progenitor cell therapy: intracoronary Doppler substudy of the TOPCARE-AMI trial. Clin Res Cardiol (2006) 95:13–22.[CrossRef][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. Rubinshtein, E. H. Yang, C. S. Rihal, A. Prasad, R. J. Lennon, P. J. Best, L. O. Lerman, and A. Lerman Coronary microcirculatory vasodilator function in relation to risk factors among patients without obstructive coronary disease and low to intermediate Framingham score Eur. Heart J., November 5, 2009; (2009) ehp459v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Bagi Mechanisms of coronary microvascular adaptation to obesity Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2009; 297(3): R556 - R567. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||