Invasive assessment of the coronary circulation: intravascular ultrasound and Doppler

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]. 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. 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]. 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. 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. Coronary flow velocity during bolus administration of acetylcholine (10−4m) 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. 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. Localized drug delivery systems: longitudinal (left) and cross-sectional (right) views. Dashed lines—arterial wall. 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. 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]. 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. 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. 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 instrumentation of the proximal and distal coronary arteries. are but do include coronary arterial and the potential to cause The Doppler signal is heavily dependent on the of the wire volume to the longitudinal and 5 from the and a position is essential to measurements. may be a particular problem with the wires that can more easily the arterial wall. Doppler wires with a volume are under Doppler wire of coronary flow velocity and coronary during saline and nitroprusside infusions. of the significant in the and of coronary angiography of the coronary anatomy is essential (Figure coronary angiography uses contrast injection of the coronary arteries to the lumen and, using coronary arterial luminal and must be taken to the artery without or of Since coronary are often and QCA should be performed in more than an is that the which the is are and this often to the of coronary angiography was used as of the methods of assessing the epicardial coronary arteries [7, it is now more used for assessing the minimal luminal area of coronary during coronary In with Doppler flow velocity QCA can the of coronary blood flow by the luminal cross-sectional area of the cross-sectional area is usually undertaken by although when are may be more appropriate and provide a more accurate assessment (see coronary assessment of luminal and imaging catheters at and have either a or a Boston the latter to although technology has The probes are into the coronary artery in the same as an angioplasty balloon under systemic (50 Intravascular ultrasound catheters are very but can coronary and intracoronary should be given before Some imaging catheters the guide wire to be which the of the guide An is essential to the coronary arteries particularly where measurements and are being in arterial during the cardiac and is particularly for determination of arterial and The of the ultrasound is not and therefore such as cardiac or should be used as The of the the catheter and a guide wire is a small will be (Figure The coronary arterial the the the and the This is not in because the is very and below the of In addition, the of the may be to and the more between the and is used to describe the volume Intravascular in a coronary artery. is that coronary arteries or arterial often a significant (Figure This is due to or where the artery to a large burden imaging can also describe the composition from through to and this may be enhanced by of the radiofrequency signal can be performed using that use (Figure a volume of tissue between the and the can be and in on-line This can provide an accurate of within the coronary arteries. arterial associated with and ultrasound views. Intravascular cross-sectional and coronary angiography to the luminal area and functional of coronary as well as the injection of contrast agents that may cause in coronary blood flow and confound measurements Moreover, drug infusion may to be and the catheter before the contrast injection Although these are not to the combined use of IVUS and the signal from the Doppler wire can cause with the IVUS catheter and and radial to on the effect (Figure This does cause significant and measurements of coronary artery cross-sectional area are The IVUS imaging catheter area can also cause significant obstruction to flow particularly in the presence of luminal of and therefore heavily arterial are not to this Moreover, IVUS provides a cross-sectional of the artery at a given time and although of the artery can be it does not permit an instantaneous assessment of the arterial However, the combined use of IVUS and Doppler wire does the functional assessment of both and resistance vessel vascular and function [8, Intravascular and coronary angiography has been widely used to the and of coronary However, as QCA has and that permit only of because QCA only the arterial lumen and the arterial wall is from a segment and does not of (Figure Intravascular ultrasound is now the of choice for the precise determination of proximal The latter also facilitates the accurate assessment of restenosis coronary although functional assessment using Doppler and wires may also be of Doppler wire measurements of coronary blood flow and velocity have been both in and in and can provide an accurate assessment of coronary flow reserve However, is coronary flow velocity measurements have only because of on arterial luminal heart rate and Although for these factors can increase the further approach to increase the and has been to and coronary flow velocity during hyperaemic flow As QCA has many potential of which may use. Some of these may be by using and that the assessment of QCA by a central assessments are in a and This does significant of that the of QCA in the of both minimal luminal and Intravascular ultrasound provides an accurate assessment of intracoronary volume [1, that is very The determination of coronary artery cross-sectional area and volume by IVUS is enhanced by of the Moreover, and measurements of volume that from by and and volume can be by large of that cause and the vessel The use of mechanical may also cause especially in vessels (Figure Moreover, vessel can also cause in measurements due to the effect of the being and the from an of an IVUS examination also a The of coronary flow reserve has main assessment of the functional of coronary and determination of the function of the coronary Although the former has been by the use of wires and the of flow coronary flow reserve to be utilized for the assessment of the coronary has been for time in the of significant functional of the coronary the coronary flow reserve may be due to of the such as in with and with left ventricular changes are likely to a of factors that include of the small vessels as well as such as of the ventricular Coronary flow reserve is in response to endothelium-independent microvascular vasodilators, such as papaverine and although adenosine is the coronary since it near in coronary vascular However, of such responses with with endothelium-dependent can provide a method of assessing function of the coronary resistance The determination of coronary blood flow responses to infusion of selective and permits the assessment of the physiological and of such as and bradykinin However, will focus here on the assessment of function. Initial methods of assessing coronary function have the epicardial vessel responses to endothelium-dependent vasodilators, such as acetylcholine substance P [7, or bradykinin [15, causes in arterial by coronary or, in the of coronary in with risk factors for vasomotor responses may be pharmacological In addition, hyperaemic endothelium-dependent flow-associated vasodilatation of the epicardial coronary arteries is also in with atherosclerosis and associated risk factors However, the mechanical and pharmacological of the may result in of dysfunction to the of the The study was of the to the influence of on coronary function. was a that the effect of the on acetylcholine induced changes in epicardial coronary and with coronary artery were at baseline and of or The that therapy was associated with a significant in function as by the of acetylcholine induced To coronary vessel function has been by determining responses in coronary blood flow, using QCA and Doppler wire, to infusions of endothelium-dependent an approach also permits the assessment of epicardial coronary function through the of epicardial coronary artery This has been used to the of dysfunction in response to acute drug such as with and are but in a small of lipid-lowering therapy was associated with in coronary microvascular function Coronary blood flow measurements combined with coronary sinus and arterial blood sampling permit the assessment of the or of factors the coronary circulation and left ventricle (see of both and and can be undertaken in this [8, and can also be used to the response of the to interventions This technique has been used to aspects of function and is by that have the of tissue in response to substance P and bradykinin infusions. This has a between tissue and atherosclerosis and of risk factors [8]. Moreover, is associated with a of bradykinin induced tissue in the coronary circulation The assessment of and has been to that have the effects of therapy and The former has been under investigation for over 10 the of IVUS and has heavily on QCA to provide an of coronary In contrast, is often in the of development and the use of IVUS to the and of the The and were the to that therapy and the and of coronary There have been several subsequent to that the of coronary atherosclerosis can be in a of using lipid-lowering therapy have on the assessment of coronary using QCA and therefore provide only a of can be by In the and were able to with over a period composition is also important and IVUS can detect in Coronary to and thrombosis to be large with of a and compared the effects of therapy with therapy in a coronary no effect was on there was a significant in the composition of the atherosclerotic was associated with an increase of the atherosclerotic a in and The development of atherosclerosis in the coronary arteries cardiac is a major cause of and coronary artery in a of within 5 However, using can be in the of within the of vasomotor responses are and, in with coronary artery do not to be with the of This is likely to be due to the and in the of coronary atherosclerosis and administration does to the dysfunction associated with although this is particularly in vessels with wall of the of restenosis angioplasty and intracoronary there has been a of in the use of IVUS to volume and This has also facilitated the assessment of to and restenosis systemic therapeutic interventions as well as local drug and delivery The study was a of the effect of therapy with on the of restenosis at IVUS examination no significant in volume within the that use of not the subsequent development of There are several such as the of with and for of that are the of on IVUS has to the of local therapy as a of In this of intracoronary a delivery catheter was the and 10 of or was locally The was the which is a for a of The no significant in restenosis is that local drug delivery will be by stents that have shown The clinical now has a of invasive and techniques with which to and the functional and responses of the coronary The invasive assessment of coronary vasomotion and blood flow has from the of coronary sinus blood flow to the more assessment of blood flow using IVUS and ultrasound techniques are likely to be utilized, especially in the of and where novel interventions are being will provide more accurate and detailed in to and and into the composition of the may be modified by therapeutic The determination of and in particular of and will be in the and of acute coronary as well as potentially therapeutic in vivo techniques are being to or as well as providing detailed composition However, in IVUS may be able to provide more detailed on the of vascular structure and function. approaches may include the use of high-resolution IVUS in with microspheres to have the potential to provide the of specific vascular cell and in This provide the of the characteristics of the and vascular wall to in vivo function. the use of higher IVUS the and of ultrasound imaging have their is likely that in imaging will or the use of and invasive imaging approaches have the potential to tissue and and it may the imaging of choice for the assessment of vascular structure and function. and are in this area by from the and the are to for assistance in the of this review. where of indicator over time, of of of the of blood and that is dependent on the and specific of the indicator and blood [46]. The and specific of blood is for between and and therefore on the indicator for and