Invasive assessment of the coronary circulation: intravascular ultrasound and Doppler

Introduction

Advances in catheter-based technology have put many innovative techniques at the disposal of the clinical investigator. Intravascular ultrasound (IVUS), in particular, has facilitated the more detailed functional and morphological assessment of the coronary circulation, and will be the major focus of this review.

Selective intracoronary drug infusion may be desirable for a number of reasons. When examining in vivo vascular responses, systemic drug administration causes concomitant effects on organs, such as the brain and kidney, and influences neurohumoral reflexes through changes in systemic haemodynamics. Intracoronary infusions have the advantage of assessing the heart and coronary circulation in relative isolation without invoking systemic effects. This is particularly important for the assessment of cardiac and coronary function which is heavily dependent on changes in the systemic vasculature and haemodynamics. In addition, relatively high doses can be administered locally which may be important for the desired physiological or therapeutic effect and may be further facilitated by the use of local drug delivery systems. Finally, combining intracoronary drug administration with coronary sinus catheterization and sampling can further extend the assessment of the coronary circulation to include additional aspects of cardiac metabolism and function.

In addition to providing functional information, IVUS provides an invasive method of assessing arterial structure and morphology. Detailed and high-resolution examination of the proximal coronary vasculature is possible with precise and accurate definition of tissue planes [1, 2]. This permits the quantitative assessment of atherosclerotic burden and composition as well as enabling the assessment of systemic therapeutic interventions targeted at reducing atherosclerosis such as lipid-lowering therapy [3, 4].

Methods

Instrumentation

Coronary arterial cannulation

As for diagnostic coronary angiography, femoral, brachial or radial artery approaches can be used for catheter insertion and drug administration. For practical reasons, the femoral route is usually the preferred site and may be associated with a lower rate of vascular complications. Since infusion protocols are often prolonged, a heparin bolus (50 units kg⁻¹) is given prior to instrumentation of the coronary arteries.

The choice of guide catheter, guide wire and method of drug delivery system will depend upon the coronary artery anatomy and the requirements of the study protocol. Appropriate equipment selection is essential to ensure technical success of the procedure as this will heavily influence factors such as the stability of catheter position and the selectivity of potential infusions. Impaction of the guide catheter in the coronary ostium due to superselection, or the use of large guide catheters, should clearly be avoided as this will impair anterograde coronary blood flow. Administration of drugs through guide catheters with side-holes is equally inappropriate. In contrast, smaller guide catheters, particularly in the presence of imaging IVUS catheters, can hinder drug administration and require the use of higher pressures to administer bolus injections or continuous infusions.

Coronary sinus cannulation

Cannulation of the coronary sinus is most easily achieved by instrumentation from subclavian or jugular vein approaches. However, these approaches do incur a small risk of pneumothorax and femoral approaches are often more desirable. Cannulation of the coronary sinus from the femoral vein can be performed by using a preformed specific 6F catheter (modified Simmons Torcon NB catheter, HNB6.0-NT-100-PW-2S-112393-BH) [5] (Figure 1) or modifying a 6F Judkins left 5 catheter [6]. To avoid atrial blood mixing, the catheter needs to be advanced, sometimes with the assistance of a guide wire, deep into the ostium and beyond the posterior interventricular vein. Adequate positioning of the catheter can be ensured by determining coronary sinus blood oxygen saturations (SaO₂ 35–50%) although the latter may rise with increases in coronary blood flow [7, 8].

Figure 1.

Cannulation of the coronary sinus from the femoral vein using a modified Simmon's catheter.

Sampling blood from the coronary sinus is appropriate only during the evaluation of the left ventricle and, particularly, during left anterior descending artery infusions [8]. Moreover, because of extensive anastamoses within the venous system of the heart, any obstruction to venous flow will cause shunting of blood to alternative drainage systems. Thus, care must taken to ensure that catheters do not impede flow in the coronary sinus since this may cause diversion of significant quantities of blood into the anterior cardiac or Thebesian veins.

Materials and drugs

Local intra-arterial drug infusion

The administration of drugs directly into the coronary arteries can be performed via the instrumenting catheter as either a bolus or continuous infusion. Bolus injections are associated with an instantaneous increase in blood flow velocity, due to the mechanical ejection of fluid down the artery, and a subsequent additional rise or fall in blood flow velocity attributable to drug action (Figure 2). Prolonged injections or large volume boluses have the potential to obscure the second phase response because of superimposition of mechanical and pharmacological flow effects as well as causing shear stress and potentially inducing flow-associated dilatation. Bolus injections should therefore be kept to a minimal volume and must be compared with control saline injections.

Figure 2.

Coronary flow velocity during bolus administration of acetylcholine (10⁻⁴ m) into the right coronary artery. (a). At baseline (time, −10 s) (b). During bolus injection (time, 0 s) (c). Ventricular standstill (time, 10 s), and (d). Hyperaemic response (time, 15 s).

Continuous infusions via the coronary guide catheter may not reliably permit selective intracoronary drug administration because of turbulence induced by blood ejection from the heart and the potential incomplete engagement with the coronary ostium. This may be a particular problem with concomitant instrumentation of the coronary vasculature, such as with IVUS catheters [9]. Therefore, continuous drug infusions should preferably be administered via a selective intracoronary catheter, such as a monorail infusion catheter [10]. Where a mechanical IVUS imaging catheter is being utilized, selective infusions can also be undertaken through the flush port of the imaging catheter [8, 11]. Consideration should also be given to the catheter dead space which can be considerable, especially with infusions via the guide catheter.

The functional assessment of endothelium-dependent vasomotion requires the administration of endothelium-dependent vasodilators, such as acetylcholine [12–15], bradykinin [15, 16] and substance P [7, 8, 14, 17], and endothelium-independent vasodilators, such as nitroprusside [8, 14, 18], papaverine [15, 18] and adenosine [19, 20]. Administration of acetylcholine and adenosine into the right coronary or dominant circumflex artery can result in atrioventricular block and transient ventricular standstill (Figure 2). If prolonged, this will confound the assessment of vasodilatation and flow responses, and continuous infusions of acetylcholine or adenosine into these arteries should be avoided.

When assessing the coronary vasomotor response by quantitative coronary angiography (QCA; see below), these concerns are further compounded by the necessity to aspirate the drug from the diagnostic or guide catheter before contrast injection [13, 14]. Moreover, many agents, especially endothelium-dependent vasodilators, have a near instantaneous onset and offset of action and performing QCA a minute after injection [16] is likely to result in misleading measurements. This is particularly the case where there is dissociation between the hyperaemic resistance vessel response and the subsequent epicardial flow associated vasodilatation.

Local intra-mural drug delivery to the coronary artery

Localized drug delivery to an isolated segment of the coronary artery can be achieved by several methods (Figure 3). The development of catheters that are able to isolate an arterial segment permits the brief passive exposure of the artery to very high concentrations of drug. In contrast, there are many angioplasty-based methods of actively instilling high local concentrations of drugs directly into the arterial wall. The former have the advantage of inducing less trauma to the vessel wall but at the expense of decreased efficiency of delivery. The local delivery of agents to the arterial wall may provide a novel approach in the prevention of angioplasty induced restenosis and thrombosis. Some of the balloon catheters described here are no longer commercially available but are discussed both for completeness and to illustrate the approaches that have been employed.

Figure 3.

Localized drug delivery systems: longitudinal (left) and cross-sectional (right) views. Dashed lines—arterial wall.

Passive

An arterial segment can be isolated using a catheter with a proximal and distal occluding balloon (Wolinsky™, USCI) and the intervening chamber can then be perfused with the agent under investigation [21, 22]. Alternatively a Dispatch™ catheter (SCIMED Life Systems) [23–26] may be used where a helical coil surrounding a polyurethane sheath is inflated within the arterial lumen and allows anterograde flow down the central lumen of the sheath. At the same time, this coil isolates a compartment between the sheath and the arterial wall which permits protracted drug administration for more than 1 h.

Active

Suffusion of the coronary artery wall can be achieved using channelled (Channel™ balloon, SCIMED/Boston Scientific; Remedy catheter, SCIMED) [27, 28], gel coated (Hydro-Plus™, Boston Scientific) [29] or porous balloons (ACS, Santa Clara, CA) [30, 31]. The infusion times are short (20–60 s) and balloon inflation pressures low (2–6 atmospheres). Efficacy of drug delivery to the arterial wall can be enhanced by the use of iontophoretic (CorTrak Medical) [32, 33] or infiltrator catheters (Infiltrator Angioplasty Balloon Catheter, Interventional Technologies) [34, 35]. The latter uses microinjection from tri-axially arranged arrays of fine needles placed between the polyurethane pads of the angioplasty balloon catheter. Coated stents [36–38] can also provide an alternative method of delivering high local concentrations over a prolonged time period due to slow drug elution. Moreover, a combined approach is possible with the delivery of drug saturated microspheres through a porous balloon catheter [39, 40].

Procedures

Functional assessment of resistance arteries

There are several invasive methods of assessing coronary resistance vessels and blood flow. The angiogram-derived corrected TIMI frame count [41] has been shown to have clinical utility especially when assessing reperfusion after acute coronary thrombosis [42]. Although it is quantitative and can detect the presence of microvascular dysfunction [43], the corrected TIMI frame count does not directly measure absolute coronary blood flow. Other techniques are under development such as the use of the radiofrequency signal decorrelation rate from IVUS imaging catheters [44, 45]. However, the main invasive methods of assessing coronary resistance vessel function and blood flow responses are reverse thermodilution catheters and Doppler flow wires.

Reverse thermodilution catheter

Before the development of methods to measure directly coronary blood flow, the indirect approach of determining coronary sinus blood flow using a reverse thermodilution catheter was utilized [46]. Computerized integration of temporal changes in temperature permit assessments of blood flow and, with modifications, can provide continuous on-line measurements of coronary sinus flow [47]. Although not providing a measure of total or absolute coronary blood flow, it can provide a useful indicator of changes in coronary blood flow [48]. However, incomplete mixing of the blood may lead to errors [49] and this technique is not widely used for the precise determination of coronary blood flow.

Intravascular Doppler

Intracoronary Doppler probes measure coronary blood flow velocity and can describe coronary resistance vessel function either as coronary flow reserve (see below and Appendix) or, when the luminal cross-sectional area is known, absolute coronary blood flow (Figure 4). Initial Doppler probes were mounted on the tip of 3F coronary catheters [50] that limited their widespread use. However, Doppler wires (Flowire™, Cardiometrics) are now available that have the same characteristics as conventional interventional guide wires (diameter 0.014 inch), but have a small piezoelectric cell (12.5 MHz) mounted on the tip which permits assessment of coronary flow velocity (Figure 4). This facilitates direct instrumentation of the proximal and distal coronary arteries. Complications are rare but do include bradycardia (right coronary artery; 1%), arterial spasm (1%) and the potential to cause dissection [51]. The Doppler signal is heavily dependent on the alignment of the wire (sample volume 10–15° to the longitudinal axis and 5 mm from the tip) and a stable coaxial position is essential to record high-fidelity measurements. Positional instability may be a particular problem with the steerable J-tipped wires that can more easily abut the arterial wall. Doppler wires with a wider arc sample volume are currently under development.

Figure 4.

Doppler wire measurement of coronary flow velocity (upper panel) and coronary angiograms (lower panel) during saline and sodium nitroprusside infusions.

Morphometric assessment of epicardial arteries

Quantitative coronary angiography

Because of the significant variability in the interpretation and analysis of coronary angiography [52, 53], computerized quantification of the coronary anatomy is essential (Figure 5). Quantitative coronary angiography uses contrast injection of the coronary arteries to outline the lumen and, using automated computerized edge detection algorithms, determines coronary arterial luminal diameter and indirectly estimates plaque burden. Care must be taken to visualize the artery without foreshortening or intrusion of overlapping branches. Since coronary stenoses are often eccentric and ellipsoidal, QCA should be performed in more than one orthogonal view. Furthermore, an assumption is made that the reference segments, against which the lesion is compared, are normal and this often contributes to the underestimation of lesion severity. Quantitative coronary angiography was used as one of the first methods of functionally assessing the conduit epicardial coronary arteries [7, 12], however, it is now more routinely used for assessing the minimal luminal area of coronary stenoses during coronary intervention. In combination with Doppler flow velocity measurements, QCA can facilitate the estimation of coronary blood flow by deriving the luminal cross-sectional area [15]. Derivation of the cross-sectional area is usually undertaken by assuming circular geometry, although when perpendicular views are obtained, ellipsoidal geometry may be more appropriate and provide a more accurate assessment (see Appendix).

Figure 5.

Quantitative coronary angiography: assessment of luminal diameter and ‘plaque load’.

Intravascular ultrasound

Ultrasound imaging catheters operate at 20–40 MHz and have either a solid state phased array (Five-64™, Endosonics) or a single rotating transducer (Ultracross™, Boston Scientific): the latter tend to produce superior images although solid state technology has improved. The probes are introduced into the coronary artery in the same manner as an angioplasty balloon under systemic heparinization (50 IU kg⁻¹). Intravascular ultrasound catheters are very safe [54] but can induce coronary spasm and intracoronary nitrate (glyceryl trinitrate 100–200 µg) should be given before imaging. Some imaging catheters allow the guide wire to be retracted which thereby removes the artefactual acoustic shadow of the guide wire. An automated pull back device (0.25–1.0 mm s⁻¹) is essential to assess systematically the coronary arteries particularly where volumetric measurements and three-dimensional reconstructions are being made. Changes in arterial dimensions occur during the cardiac cycle and ECG-gating is necessary, particularly for determination of arterial compliance and distensibility [55–57].

The orientation of the ultrasound image is not predetermined and therefore landmarks such as pericardial reflections, cardiac veins or side branches should be used as reference points. The centre of the image represents the catheter blank and if a guide wire is present, a small acoustic arc will be seen (Figure 6). The normal coronary arterial image gives the so-called ‘three-layered’ appearance representing the intima, the echolucent media and the adventitia. This three-layered appearance is not seen in young subjects because the initima is very thin (∼170 µm) and below the resolution of current devices. In addition, the inner border of the media (the internal elastic lamina) may be difficult to identify and the more echogenic interface between the adventitia and external elastic lamina is used to describe the plaque volume [58, 59].

Figure 6.

Intravascular ultrasound: image interpretation in a normal coronary artery.

It is recognized that angiographically normal coronary arteries or arterial segments often contain a significant plaque load [55, 60–62] (Figure 7). This is due to adaptive or ‘Glagovian’ remodelling [63] where the artery expands to accommodate a large plaque burden [64]. Ultrasound imaging can also describe the plaque composition from soft fibrofatty plaques, through fibromuscular plaques to calcified hard plaques [55, 59, 65–68] and this may be enhanced by spectral analysis of the radiofrequency signal [69]. Three-dimensional reconstruction can be performed using computerized systems that use digitized ECG-gated images (Figure 8). Using a contour detection algorithm, plaque volume (volume of tissue lying between the intima–lumen interface and the external elastic lamina) can be automatically quantified [1], and in some cases, on-line [70]. This can provide an accurate index of plaque load within the coronary arteries.

Figure 7.

Glagovian arterial remodelling associated with atherosclerosis: angiographic and intravascular ultrasound (IVUS) views.

Figure 8.

Intravascular ultrasound: cross-sectional views (top left; arrow shows plaque) and three dimensional reconstruction (bottom right).

Variations in methodology

Functional assessment

Quantiative coronary angiography, intravascular ultrasound and Doppler

Quantitative coronary angiography tends to underestimate the luminal area [71, 72] and functional severity of coronary stenoses [73] as well as necessitating the injection of vasoactive contrast agents that may cause alterations in coronary blood flow and confound measurements [74]. Moreover, drug infusion may need to be interrupted and the catheter aspirated before giving the contrast injection [14]. Although these limitations are not applicable to the combined use of IVUS and Doppler, the signal from the Doppler wire can cause some interference with the IVUS catheter and produces discrete and fleeting radial striae to appear on imaging: the so-called ‘star burst’ effect (Figure 9). This does not, however, cause significant image loss and measurements of coronary artery cross-sectional area are unaffected. The IVUS imaging catheter (cross-sectional area ∼0.8 mm²) can also cause significant obstruction to flow particularly in the presence of luminal stenoses of ≥70% and therefore heavily diseased arterial segments are not suited to this approach. Moreover, unlike QCA, IVUS provides a single cross-sectional image of the artery at a given time point, and although three-dimensional reconstructions of the artery can be performed, it does not permit an instantaneous assessment of the entire arterial tree. However, the combined use of IVUS and Doppler wire does facilitate the functional assessment of both conduit and resistance vessel vascular and endothelial function [8, 57, 75–78].

Figure 9.

Intravascular ultrasound: image distortion and interference.

Morphometric assessment

Quantiative coronary angiography and intravascular ultrasound

Quantitative coronary angiography has been widely used to determine the progression and regression of coronary plaque load following intervention [79, 80]. However, as already indicated, QCA has some inherent limitations and inaccuracies that permit only crude estimates of plaque load [81]. These inaccuracies occur because QCA only assesses the arterial lumen and the arterial wall is extrapolated from a reference segment and does not take account of ‘Glagovian’ remodelling [63] (Figure 7). Intravascular ultrasound is now the modality of choice for the precise determination of proximal atheromatous plaque volume. The latter also facilitates the accurate assessment of restenosis following percutaneous coronary intervention [38] although functional assessment using Doppler and pressure wires may also be of benefit.

Reproducibility

Doppler wire

Doppler wire measurements of coronary blood flow and velocity have been validated both in vitro and in vivo [82] and can provide an accurate assessment of coronary flow reserve [20, 83–86]. However, whilst short-term reproducibility is good [87], coronary flow velocity measurements have only modest long-term reproducibility because of its heavy dependence on arterial luminal area, heart rate and aortic pressure [88]. Although correction for these factors can increase the reproducibility [88], one further approach to increase the sensitivity and reproducibility has been to construct aortic pressure and coronary flow velocity plots during hyperaemic flow [89].

Quantiative coronary angiography, intravascular ultrasound and plaque volume

As already identified, QCA has many potential sources of error [81, 90] which may limit its use. Some of these drawbacks may be overcome by using improved and standardized methodologies [81, 90] that incorporate the assessment of QCA parameters by a central reference core laboratory. Such assessments are made off line in a standardized, blinded and prespecified manner [91]. This does not, however, remove significant margins of error that hamper the reproducibility of QCA [81, 90, 92] in the measurement of both minimal luminal diameter and plaque volume.

Intravascular ultrasound provides an accurate assessment of intracoronary plaque volume [1, 2, 58, 59, 70] that is very reproducible [2, 70, 93–95]. The determination of coronary artery cross-sectional area and plaque volume by IVUS is enhanced by ECG-gating of the images [2, 70]. Moreover, three-dimensional reconstructions and computerized edge detection algorithms facilitate measurements of plaque volume that differ little from those obtained by manual contour tracing and analysis [2]. Image analysis and plaque volume determinations can be hampered by large areas of heavy plaque calcification that cause acoustic shadows and mask the underlying vessel structure. The use of mechanical transducers may also cause image disruption called NURD, Non-Uniform Rotational Distortion, especially in tortuous vessels (Figure 9). Moreover, marked vessel curvature can also cause inaccuracies in volumetric measurements due to the effect of the inner curve being expanded and the outer curve compressed. Three-dimensional reconstructions from an automated pullback of an IVUS examination also assume a linear coaxial alignment.

Study of diseases and drugs

Coronary flow reserve

The measurement of coronary flow reserve has two main applications: assessment of the functional severity of coronary stenoses and determination of the function of the coronary microvasculature. Although the former has been largely superceded by the use of pressure wires and the measurement of fractional flow reserve, coronary flow reserve continues to be utilized for the assessment of the coronary microvasculature.

It has been appreciated for some time that, even in the absence of significant functional stenoses of the coronary arteries, the coronary flow reserve may be impaired due to structural abnormalities of the microvasculature, such as in patients with hypertension [96], diabetes mellitus [97], syndrome X [98], hyperlipidaemia [99] and aortic stenosis with left ventricular hypertrophy [100]. These changes are likely to represent a combination of factors that include structural abnormalities of the small vessels as well as physical extravascular forces, such as elevation of the ventricular end diastolic pressure [101].

Coronary flow reserve is measured in response to endothelium-independent microvascular vasodilators, such as adenosine, papaverine and sodium nitroprusside, although adenosine is the favoured coronary vasodilator since it produces near maximal reduction in coronary vascular resistance. However, comparisons of such responses with those obtained with endothelium-dependent vasodilators can provide a method of assessing endothelial function of the coronary resistance vessels.

Endothelial function

The determination of coronary blood flow responses to infusion of selective antagonists and inhibitors permits the assessment of the physiological and pathophysiological role of endogenous mediators, such as nitric oxide [14, 102] and bradykinin [103]. However, we will focus here on the assessment of endothelial function.

Epicardial coronary arteries

Initial methods of assessing coronary endothelial function have determined the epicardial conduit vessel responses to endothelium-dependent vasodilators, such as acetylcholine [12, 13], substance P [7, 8] or bradykinin [15, 16]. Acetylcholine causes paradoxical vasoconstriction in arterial segments affected by coronary atheroma [12] or, in the absence of overt coronary atheroma, in patients with risk factors for atheroma formation [104]. These abnormal vasomotor responses may be reversible following suitable pharmacological intervention [105]. In addition, hyperaemic endothelium-dependent flow-associated vasodilatation of the epicardial coronary arteries is also impaired in patients with atherosclerosis [18] and its associated risk factors [106]. However, the mechanical and pharmacological stimulation of the endothelium may result in differing degrees of apparent endothelial dysfunction according to the nature of the insult [10, 107, 108].

The TREND study [13] was one of the first studies to investigate the influence of intervention on coronary endothelial function. It was a multicentre double-blind randomized controlled trial that examined the effect of the angiotensin converting enzyme inhibitor, quinapril (40 mg daily), on acetylcholine induced changes in epicardial coronary diameter. A hundred and five patients with coronary artery disease were assessed at baseline and following 6 months of quinapril or placebo therapy. The investigators found that quinapril therapy was associated with a significant improvement in endothelial function as demonstrated by the abolition of acetylcholine induced vasoconstriction.

Coronary resistance arteries

To date, coronary resistive vessel endothelial function has been assessed by determining responses in coronary blood flow, using QCA and Doppler wire, to infusions of endothelium-dependent vasodilators. Such an approach also permits the simultaneous assessment of epicardial coronary endothelial function through the measurement of epicardial coronary artery diameter.

This methodology has been used successfully to demonstrate the improvement of endothelial dysfunction in response to acute drug administration, such as with oestrogen [109], l-arginine [110, 111], vitamin C [106] and reduced glutathione [112]. Long-term studies are lacking but in a small poorly controlled study, 6 months of lipid-lowering therapy was associated with improvements in coronary microvascular endothelial function [113].

Release and extraction across the coronary circulation

Coronary blood flow measurements combined with coronary sinus and arterial blood sampling permit the assessment of the release or extraction of factors across the coronary circulation and left ventricle (see Appendix). Measures of both basal and stimulated, release and extraction can be undertaken in this manner [8, 15, 48, 114], and can also be used to assess the metabolic response of the myocardium to various interventions [115, 116].

This technique has been used to assess other aspects of endothelial function and is exemplified by studies that have measured the release of endothelium-derived tissue plasminogen activator in response to substance P [8] and bradykinin [15] infusions. This work has established a link between impaired tissue plasminogen activator release and atherosclerosis and some of its risk factors [8]. Moreover, angiotensin converting enzyme inhibition is associated with a marked potentiation of bradykinin induced tissue plasminogen activator release in the coronary circulation [15].

Atherogenesis and plaque regression

The assessment of atheromatous plaque progression and regression has been applied to studies that have investigated the effects of lipid lowering therapy and transplant vasculopathy. The former has been under investigation for over 10 years, predated the availability of IVUS and has relied heavily on QCA to provide an index of coronary atheromatous load. In contrast, transplant vasculopathy is often angiographically silent in the early phases of development and necessitates the use of IVUS to delineate the consequences and severity of the disease process.

Lipid lowering therapy and plaque regression

The FATS [79] and Lifestyle Heart [80] trials were amongst the first trials to show that aggressive lipid lowering therapy and lifestyle modifications could halt the progression, and even induce regression, of coronary atherosclerosis. There have been several subsequent studies to demonstrate that the progression of coronary atherosclerosis can be reduced in a broad spectrum of patients using lipid-lowering therapy [117, 118]. These studies have relied on the assessment of coronary atheroma using QCA and therefore provide only a crude estimate of plaque load.

Plaque regression can be accurately defined by IVUS. In the first long-term study, Takagi and colleagues were able to demonstrate plaque regression with pravastatin over a 3 year treatment period [3]. Plaque composition is also important and IVUS can detect differences in plaque density. Coronary plaques prone to rupture and thrombosis tend to be large eccentric lesions with echolucent zones indicative of a lipid-rich core [119, 120]. Schartl and colleagues [121] compared the effects of 12 months aggressive lipid lowering therapy with standard lipid lowering therapy in 131 patients undergoing a percutaneous coronary intervention. Whilst no effect was seen on plaque volume, there was a significant change in the apparent composition of the atherosclerotic plaque. Aggressive LDL cholesterol reduction was associated with an increase echogenicity of the atherosclerotic plaque indicating a reduction in lipid content and greater plaque stability.

Transplant vasculopathy

The development of accelerated atherosclerosis in the coronary arteries following cardiac transplantation, so-called transplant vasculopathy, is a major cause of long-term morbidity and mortality. Angiographically evident coronary artery disease occurs in nearly a half of transplant recipients within 5 years [122]. However, using IVUS, heterogenous intimal thickening can be detected in the majority of patients within the first year of transplantation [77, 123, 124]. Endothelial vasomotor responses are heterogenous and, unlike those in patients with coronary artery disease [125], do not appear to be correlate with the degree of intimal thickening [77, 108, 126]. This is likely to be due to the differing aetiological and pathogenetic process involved in the formation of coronary atherosclerosis and immunologically mediated transplant vasculopathy. Acute l-arginine administration does appear to improve the endothelial dysfunction associated with transplant vasculopathy although this is particularly evident in vessels with normal wall morphology [111].

Restenosis

Because of the problems of restenosis following angioplasty and intracoronary stenting, there has been a great deal of interest in the use of IVUS to quantify restenotic plaque volume and neointimal hyperplasia [127]. This has also facilitated the assessment of strategies to prevent neointimal hyperplasia and restenosis including systemic therapeutic interventions [128] as well as local drug and gene transfer delivery systems [129, 130].

The ERASER study [131] was a double-blind randomized controlled trial of the effect of antiplatelet therapy with abciximab on the occurrence of in-stent restenosis at 6 months. IVUS examination identified no significant difference in plaque volume within the stented segments, suggesting that procedural use of abciximab did not prevent the subsequent development of in-stent restenosis. There are several ongoing trials, such as the Reversal of Atherosclerosis with Lipitor (REVERSAL) [4] and NOrvasc for Regression of Manifest Atherosclerotic Lesions (NORMALISE) trials [132], that are comparing the impact of various cardiovascular therapies on IVUS determined plaque volume.

One preliminary study, ITALICS [128], has attempted to address the issue of local antimitotic gene therapy as a strategy of preventing restenosis. In this double-blind randomized controlled trial of 90 patients who received intracoronary stent implantation, a delivery catheter was positioned across the stent and 10 mg of antisense oligoDNA or placebo vehicle was locally administered. The antisense DNA was directed against the c-myc proto-oncogene which is a transcription factor for cyclin D, a key mediator of cellular mitosis. The investigations reported no significant differences in restenosis plaque volume. It is likely, however, that local drug delivery systems will be superseded by drug-eluting stents that have shown early promise [38].

Conclusion and future directions

The clinical researcher now has a range of invasive and noninvasive techniques with which to assess and investigate the functional and haemodynamic responses of the coronary circulation. The invasive assessment of coronary vasomotion and blood flow has progressed from the imprecise measures of coronary sinus blood flow to the more direct assessment of blood flow using IVUS and Doppler.

These ultrasound techniques are likely to be increasingly utilized, especially in the expanding field of applied molecular biology, and where novel antiatherogenic interventions are being evaluated. Future trials will provide more accurate and detailed information in relation to plaque remodelling and regression, and perhaps give insights into how the composition of the plaques may be modified by therapeutic interventions.

The determination of plaque characteristics, and in particular areas of plaque disruption and inflammation, will be critical in understanding the pathogenesis and resolution of acute coronary syndromes, as well as potentially guiding therapeutic interventions. Many in vivo techniques are being developed to identify vulnerable or inflamed plaques as well as providing detailed information about plaque composition [133]. However, future developments in IVUS may be able to provide more detailed information on the state of vascular structure and function. Such approaches may include the use of high-resolution IVUS in combination with antibody labelled echocontrast microspheres [134]. Antibody binding to selected antigens would have the potential to provide information regarding the surface expression of specific vascular cell proteins and receptors in vivo. This would provide the exciting prospect of relating the structural characteristics of the endothelium and vascular wall to its in vivo function.

Despite the use of higher frequency IVUS transducers, the spatial resolution and physical properties of ultrasound imaging have their limitations. It is likely that advances in magnetic resonance imaging will complement, or even displace, the use of IVUS. Both noninvasive [135] and invasive [136] magnetic resonance imaging approaches have the potential to improve dramatically tissue resolution and characterization, and it may become the imaging modality of choice for the assessment of vascular structure and function.

Appendix

Mathematical calculations

Coronary blood flow

Reverse thermodilution catheter

where V = volume (ml) of indicator infused over time, t (min); T_b = temperature of blood; T_i = temperature of indicator; T_m = temperature of the mixture of blood and indicator; k = a constant that is dependent on the density and specific heat capacity of the indicator and blood [46]. The density and specific heat capacity of blood is constant for haematocrits between 0.30 and 0.60 and therefore varies mainly depending on the indicator used: for 0.9% saline, k = 1.19 and 5% dextrose, k = 1.17.

Quantiative coronary angiography and Doppler

Assuming circular geometry:

where d = coronary arterial diameter (mm) and APV = average peak velocity (cm/s). With a parabolic velocity profile, mean blood flow velocity equates to half the APV [82].

Assuming elliptical geometry [18]:

where d₁ and d₂ = coronary arterial diameters (mm) in two perpendicular views.

Intravascular ultrasound and Doppler

Assuming a parabolic velocity profile [82]:

where CSA = coronary arterial cross-sectional area (mm²) and APV = average peak velocity (cm/s).

Estimated net release/extraction from the coronary circulation

Assuming that the coronary sinus drains exclusively from the left anterior descending coronary artery territory [8, 15]:

where CBF = left anterior descending coronary artery blood flow (ml min⁻¹), CS_Conc = plasma coronary sinus concentration (AU/ml), Art_Conc = plasma arterial/aortic concentration (AU/ml), and Hct = haematocrit.