Book Chapter: Functional Assessment of Coronary Artery Disease

Hyperemia Myocardial blood flow is regulated by changes in vascular resistance at the level of the arterioles. As the oxygen demands of the myocardium increase, the arteriole beds dilate to increase blood flow to the region. Similarly, when a flow-limiting stenosis is present, the distal microvasculature must compensate for this by being continuously dilated to preserve resting basal blood flow. Then, when myocardial oxygen needs to increase, the already-dilated microvasculature cannot supply a greater blood flow to meet the demand. Pressure and flow are related to each other by vascular resistance. At rest, the myocardium requires only a minimal blood supply and the arterioles remain constricted. During exercise, however, these arterioles dilate, myocardial resistance is reduced to a minimum, and a greater volume of blood can reach the muscle. When a vessel is in a state of maximum dilation, it is said to be in a state of hyperemia. If an artery is blocked by a stenosis, the myocardium receives less blood and, therefore, less oxygen than it requires. To compensate for this, these microvessels dilate as they do during exercise. In a vessel with a significant stenosis, the microvasculature is in a constant state of compensatory dilation.¹ Vascular resistance varies due to many factors such as exercise, ischemia, arterial blood pressure, vasomotion and contrast medium injections. Unless vascular resistance is constant, functional severity of a lesion cannot be accurately assessed. With maximum vasodilatation of the coronary vasculature, maximum flow is achieved and the myocardial resistance is minimal and constant. Maximum dilatation occurs during physical exertion, but in the confines of a cardiac catheterization laboratory, this can be achieved by administering a vasodilatory drug. Several drugs produce a hyperemic response in the manner described above. Nitroglycerine and other nitrates cause microvascular hyperemia, but their main effect is to dilate the large epicardial vessels, increasing their cross-sectional area. This dilatory response reduces the speed of blood flow, negating the effect of any increased flow that may be related to microvascular hyperemia. Papaverine has also been used in many studies, with the most common side effect being prolongation of the Q-T interval. Rare cases of Torsade de Pointes have been reported with its use, and it is rarely used today. Adenosine, commonly used for breaking supraventricular tachycardia, has been found to be a fast-working hyperemic agent, and it has a short half-life, making it ideal for coronary hyperemic studies. One of the few side effects of adenosine is transient bradycardia and heart block, usually lasting only a few seconds. Dosing and administration of hyperemic agents vary. Some practitioners prefer to administer the agents as a rapid IC bolus, while others prefer to use an IV infusion to achieve a more prolonged, steady-state effect. At the Cleveland Clinic, the protocol for IC administration is to dilute 6 mg of adenosine into a 250 mL bag of D5W, providing a concentration of 24 µg/mL. The cardiologist administers initial doses of 36-48 µg IC for left coronary artery (LCA) branches, and 24-36 µg IC for the right coronary artery (RCA). If the injection is repeated, the dose is increased at the physician’s discretion. For IV administration, the infusion is prepared by withdrawing 16 mL of fluid from a 50 mL bag of D5W, then adding 48 mg (16 mL of adenosine concentration 3 mg/mL). The infusion is preferably administered through a central line, however, it is most often given through a 20 g (or larger) IV catheter located in the antecubital vein. The IV drip is very rapid, at a dose of 140 µg/kg/minute.² Due to the high cost of adenosine, some centers are re-examining the use of papaverine for inducing hyperemia. IC papaverine will produce hyperemia similar to that of IV adenosine. Papaverine is administered IC in dosages of 10-15 mg for the LCA, and 5-10 mg for the RCA. Peak hyperemic effects with IC papaverine occur about 30 seconds after administration and may last an additional 60-90 seconds. Additional considerations for the use of papaverine include its incompatibility with heparin, iodinated contrast agents and ioxaglate meglumine (Hexabrix ^®, Mallinckrodt, Saint Louis, Missouri). When papaverine is combined with one of these, the resulting solution is milky or opalescent. Non-heparinized flush solutions and nonionic contrast must be utilized. Doppler Blood Flow Measurement The Doppler theory is named after the Austrian physicist who first described it, Christian Johann Doppler (1803-1853). Doppler works on the following principle: when an observer moves towards the source of a sound, the tone of the sound will be heard at a higher frequency than if the observer remains stationary. The same is also true if the observer remains stationary and the source of the sound moves. This is why when a car is driven toward an observer, the tone of the engine changes. It becomes higher-pitched as it approaches, and then lower-pitched as it moves away from the observer. The alteration in tone can be measured as a change in frequency of the received sound waves, and with the Doppler formula, the speed of the object can be calculated. It is therefore possible to measure the speed of an approaching or receding object by bouncing a sound wave of known frequency off the object and accurately measuring the frequency of its returning echo. In 1977, the first Doppler measurement was made inside a coronary artery using a modified 8 Fr catheter, which had obvious restrictions due to its size. Technological advances have enabled the miniaturization of the necessary components, making it more feasible for IC applications. From the tip of a 0.014 inch guidewire, a Doppler crystal sends out sound waves (Figure 10-1), which are returned as echoes reflected off circulating red blood cells. The velocity measurement of the cells is done in a sample area about 5 mm from the tip so that the presence of the wire does not affect the flow of the cells to any great extent. The guidewire is attached to a monitor, which translates the signals it receives into a variety of readings to quantify the state of the disease. Indications for use. Lesion assessment. IC Doppler quantitatively assesses the severity of a stenosis and can therefore assist the physician’s decision-making. It is of particular assistance when a lesion appears to be of borderline significance angiographically. Several Doppler measurements may be employed to assess a stenosis, but the coronary flow reserve (CFR) is the most commonly used. CFR measures the change in the velocity of the blood flow to determine the extent of microvascular dilation. When hyperemia is induced in a healthy vessel, more than twice as much blood flows through the microvasculature. If the same bolus is given in a vessel with a significant stenosis (wherein the microvasculature is already in a permanently dilated state), the result will be less than a two-fold increase in blood flow. In fact, when the CFR is greater than 2.5, no intervention is indicated. Another measurement method is to simply measure the speed of the blood flow proximal to the lesion and then directly distal to it. A proximal/distal velocity ratio can be derived, which is considered significant if it is > 1.7.³ One advantage of this method is that the hemodynamic effect of a stenosis can be effectively isolated, even in the presence of a series of obstructions. Another method is the diastolic/systolic velocity ratio (DSVR). It has been found that a lesion will reduce diastolic blood flow and increase relative systolic flow.¹ The average diastolic and systolic peak velocities are measured and expressed as a ratio. The value can then be compared with a table of normal DSVRs, which are different for the different sections of each vessel. Ostial lesion severity is often difficult to quantify by angiography. It has been found, however, that ostial lesion severity can be measured by taking the blood flow velocity within the lesion (jet velocity), and comparing that with the distal flow velocity.⁴ Collateral flow can be shown quite clearly in most cases by angiography, but it can be quantified by Doppler. Collateral flow is displayed on the monitor by shading below the 0 line, indicating blood flow towards the wire tip rather than away from it, as is usually the case. This is most useful when assessing flow within graft recipient vessels to assess graft and primary lesion patency. Once the signal has been acquired, it becomes very important for the assistant to perform an accurate and rapid injection of adenosine (normally 18 µg into the LCA or 12 µg into the RCA), followed by a rapid injection of normal saline (2-3 mL). The Doppler system is then set to search for the maximal or peak flow velocity. Evaluating interventional results. Even more so than with stenosis evaluation, assessing the effectiveness of angioplasty can prove difficult with angiography. Intimal flaps, associated with coronary dissection, can be difficult to pick up on the radiograph. As IVUS has shown, every angioplasty procedure damages the intima to some extent, causing the angiographic lumen to appear hazy. A CFR of 2.5 or more is an indicator of a successful intervention.⁵ Since the Doppler guidewire can quite safely be left in position throughout the intervention, periodic CFR measurements can be obtained to assist in determining the therapeutic endpoint. Other uses. Microvascular disease can be detected in stenosis-free vessels through the use of CFR. If a bolus of adenosine is given in a stenosis-free vessel and the resulting increase in blood flow is less than two times what it was before the injection, microvascular disease (Syndrome X) can be suspected. Research applications. In vivo quantitative analysis of pharmaceuticals and interventional devices requires precise measurements. Doppler systems provide researchers with a tool that can evaluate the effectiveness of a drug or a device affecting coronary blood flow in a reasonably objective fashion in the setting of the cardiac catheterization laboratory. It is theoretically possible to measure the actual volume of blood flowing through a vessel with the following formula: Flow = CSA x FVi x Heart rate where CSA is the vessel’s cross-sectional area and FVi is the flow velocity integral (or mean flow velocity). This assumes, however, that the vessel’s diameter remains constant, the tip of the wire is measuring at a constant angle and no branches or vessel wall irregularities are interfering with the flow. Because it is difficult to measure exactly the first two of these factors over a period of time, the Doppler measurements are most often taken as relative rather than absolute. Components of the FloMap Systen The following is a guide to the use of the Doppler FloWire and FlowMap System (Volcano Therapeutics, Inc., Rancho Cordova, California). For specific functions and operating techniques, the operator’s manual, which is provided with each unit, should be followed. The first-generation Doppler FloMap units are free-standing floor units that can be moved from room to room. Second-generation, integrated units are often mounted under or next to the fluoroscopic monitors. Whether free-standing or integrated, the coronary Doppler FloWire system is comprised of a guidewire, a monitor and the connections. The distal, sterile component is the guidewire, which is similar to a conventional interventional guidewire, with the exception of a Doppler crystal on the distal tip and an adapter, which is connected to the wire during measurement and is disengaged during wire manipulation and placement. The proximal end of the adapter is attached to the patient interface cable, which in turn is connected to the monitor (Figure 10-2). The patient interface cable is not sterile, but needs to remain in the field. It is necessary to cover this and any exposed part of the patient cable with a sterile sleeve. The monitor collects and interprets the signals sent by the guidewire and translates them into a graphic display with numerical values. A video recorder allows what is displayed on the screen to be archived for later reference, and a thermal printer permits hard copy measurements to be entered into the chart. The patient’s ECG must be saved into the FloMap system as well. Signal acquisition. The patient should be heparinized per institutional protocol prior to inserting the Doppler FloWire. Once the FloWire has been positioned across the lesion, a clear signal must be obtained. A good signal relies on correct placement of the guidewire within the vessel. A good signal has a sharp edge of reasonably uniform shading. Circulating red blood cells are not all moving at exactly the same velocity, so the Doppler FloMap system measures a velocity range. Therefore, the Doppler image is displayed as a shape rather than a single line. Signal quality can be affected by the FloWire tip being too close or touching the vessel wall (Figure 10-3), in which case the Doppler will be measuring the movement of the wall as well as the blood vessels. Figure 10-4 shows the display screen of a FloMap monitor. At the top of the screen is the ECG, from which the diastolic and systolic divisions of the measurement spectrum are taken. Under the ECG is the monitor’s display of the range of velocities of the red blood cells. This reading was made in a healthy, proximal left anterior descending coronary artery and displays a good range of flows. Note that the upper edge of the shaded area is sharp and well defined. The white dotted line that runs along the upper edge of the shaded area is called the envelope, and this indicates what is being measured as the peak velocity. Note also that there is more flow, even a peak, during diastole. Here the aortic valve has closed, and the elasticity of the vessels pushes the blood peripherally. The vertical axis is showing the velocity in cm/sec. The horizontal axis shows time in seconds. It is possible to change this scale for optimal display. THR, or threshold, is the amount of background noise that is filtered out. If the Doppler signal is quite weak, the threshold can be decreased, but this means that there will be more background noise and a less clear display because fewer of the fine, obstructive signals are being filtered out. The threshold value should be adjusted for each patient. The optimum setting is typically in the range of 0-30. In addition to a visual representation of the signal, an audible Doppler tone is heard. If a good signal has been obtained, there is a swishing sound, which is the rush of blood in the vessel. A whistle or deeper, thumping sound is demonstrative of a wire that is touching or too close to the vessel wall. Although these audible signals can be useful in ensuring correct positioning of the wire, they can prove to be a distraction and may easily be shut off. Limitations of the Doppler FloWire. There are a few difficulties associated with the technique of measuring CFR. Large overlaps exist between the normal and abnormal Doppler flow values, and there is no standard reference value of a normal coronary velocity reserve. CFR decreases significantly with heart rate and blood pressure.⁶ The Doppler FloWire must be positioned precisely in the vessel lumen to obtain a good signal, and is very sensitive to motion. IC injection of the hyperemic agent can disrupt the wire position and the signal. Blood velocity measurements are affected by both changes in the large epicardial vessels and the microvasculature, making it difficult to assess the functional severity of an ambiguous lesion, particularly in diabetic patients. Because of these limitations, and the often-difficult reproducibility of the results, Doppler CFR and velocity measurements have fallen out of favor in recent years. A newer technique of IC pressure measurement has been developed and is now the favored method of physiologic coronary disease assessment. Intravascular Pressure Measurement After the introduction of the first over-the-wire percutaneous transluminal coronary angioplasty (PTCA) balloons, trans-stenotic pressure gradients were recorded to guide the progress of the dilatation. Aortic pressure was obtained from the guide catheter and was used as the reference measurement. A pressure measurement was also obtained through the guidewire lumen of the balloon catheter, assessing the vessel distal to the lesion. Physicians typically used a postdilatation gradient of less than 15 mmHg to indicate a satisfactory result. There were a number of limitations to this technique. The initial over-the-wire balloon catheters had shafts with diameters of 3.5 Fr, and their large cross-sectional areas would often produce unpredictable pressures or even totally obstruct a stenosis. The original 9 Fr guide catheters had inner diameters of 0.072 inch, and the balloon catheters would dampen the aortic pressures. Also, only low-frequency responses could be obtained with fluid-filled catheters and transducer systems. Because of these limitations and the rapid development of online digital quantitative coronary analysis (QCA), interest in intraluminal pressure measurements waned. It was hoped that QCA alone would provide definitive diagnosis. QCA did live up to those expectations to some extent, but as cardiologists began to tackle more complex lesions and multivessel arterial disease, it became clear that there was a need for a reliable measurement of the functional significance of coronary lesions. Coronary Pressures and Fractional Flow Reserve When assessing the significance of a coronary lesion, the most basic questions are: How much blood is actually supplying the demands of the heart? At what point do the demands exceed the supply? How can this parameter be evaluated easily and accurately? As discussed earlier, coronary pressures were measured frequently when PTCA was in its infancy, but practical application and deriving true physiologic data was not possible with the available technology. Technological advances have enabled the miniaturization of transducer elements, making it more feasible for IC applications. Healthy coronary arteries and their associated microvessels dilate in response to exercise. When the coronary artery becomes diseased, there is a drop in pressure across the lesion and a compensatory dilatation of the microvasculature. As oxygen demands increase, the coronary artery constricts, and the pressure drop across the lesion increases. Since the microvessels are already in a dilated state, there is limited (or no) capacity left to meet the increased demands. This results in ischemia and chest pain. Myocardial fractional flow reserve (FFR) can be defined as the maximal myocardial blood flow in the presence of a stenosis in the supplying coronary artery, divided by the normal blood flow. At maximum hyperemia: FFR = Pd / Pa where Pd equals mean distal pressure, and Pa equals mean arterial pressure. Two systems are currently available for clinical use: the RADI Pressure Wire®/RADI Analyzer®, and the Volcano Therapeutics, Inc. WaveWire/ WaveMap systems. Indications for use. Lesion assessment. The most common indication for measuring coronary pressure and FFR is evaluating a mild-to-moderate stenosis to assess whether it is responsible for reversible ischemia. Like Doppler CFR measurements, FFR can help to quantitatively assess the functional severity of the obstruction. Unlike CFR, FFR is a lesion-specific index, with a clear normal value of 1.0 in every patient and every coronary artery. It has been repeatedly demonstrated that a FFR of 0.75, the angioplasty was performed as planned (144 patients). Clinical follow-up occurred at 1, 3, 6, 12 and 24 months. Event-free survival at 24 months was similar in the randomized group: 89% deferred versus 83% angioplasty. This shows that patients with a coronary stenosis and an FFR > 0.75 derive no clear cut benefit from undergoing an intervention.⁷ FFR may also be used to determine the viability of myocardial tissue post-myocardial infarction (MI). In patients with a recent MI, the occurrence of cardiac events is often related to coronary re-occlusion, which cannot be predicted by angiography. The present data extends the validity of the 0.75 threshold value of FFR as a surrogate for noninvasive stress testing to patients with a prior MI. If the coronary angiogram shows a mild-to-moderate lesion in the culprit vessel, performing FFR while the patient is in the catheterization laboratory eliminates the need for an expensive (though noninvasive) test after discharge.⁸ Evaluating interventional results. In a multicenter registry of 750 patients, FFR was assessed after angiographically successful stent implantation. At six months follow-up, FFR was the most significant predictor of all types of adverse events. FFR normalized (> 0.95) in 36% of the patients, with an adverse event rate of 4.9%. In 32% of the patients, the post-stent FFR measured 0.90-0.95, with an adverse event rate of 6.2%. For patients with FFR measuring Components of the Intracoronary Pressure Wire Systems Similar to the coronary Doppler FloWire system, the pressure guidewire units are comprised of a guidewire, a monitor and connections. Unfortunately, the units and their guidewires cannot be used interchangeably. The following sections describe the use of the RADI Analyzer/PressureWire and Volcano Therapeutics’s WaveMap/WaveWire/ SmartWire systems. For specific functions and operating techniques, consult a company representative or the unit’s operator’s manual. RADI Analyzer®/PressureWire® System. The distal, sterile component is the guidewire. It is similar to a conventional interventional guidewire, with the exception of three microsensor elements 3 cm proximal to the distal tip at the transition of the radiopaque and radiolucent segments. Each of the three sensor elements has a specific function: one measures pressure/FFR, the second is designed to measure a thermodilution-derived CFR, and the third is a temperature sensor. The pressure transducer is a silicon, piezoresistive microsensor coupled in a Wheatstone bridge, with a working range of 30-300 mmHg. The RADI PressureWire is available in both 175 cm and 300 cm lengths. A 6-foot adapter/contact cable connects the PressureWire to the RADI Analyzer during pressure measurements, and can be disengaged during wire placement and manipulation. The RADI Analyzer is a portable computer system that is mounted on an IV pole and interfaces with the cardiac catheterization laboratory’s hemodynamic system. It collects and interprets the signals sent by the guidewire micromanometer and allows the arterial waveform from the guide catheter and the PressureWire waveform to be simultaneously displayed on both the RADI Analyzer and the cath lab hemodynamic system (Figure 10-6). A remote control allows input of patient data and operation of the system. An optional thermal printer permits hard copy measurements to be entered into the chart. The RADI Analyzer will store a number of patient recordings, and optional RADI View software allows digital transfer of information to a PC for future review, editing, report into spreadsheets, and PowerPoint slide presentations. The patient should be heparinized per institutional protocol prior to inserting the PressureWire. The following steps may be used as a quick setup and may vary depending on the institution’s hemodynamic system. 1. Plug in and turn on the RADI Analyzer; a software boot and series of self checks will take about 30 seconds to complete. 2. Connect pressure inputs and outputs. Pa In connects to the guide catheter transducer. The Pa Out cable connects into the pressure channel 1 input of the hemodynamic system. The PressureWire Out cable connects into the pressure channel 2 input of the hemodynamic system. The wire adapter/ contact cable connects into the RADI Analyzer. 3. Select a cath lab hemodynamic system program that will allow display of two separate channels with both phasic and mean waveforms on a 200 mmHg scale (most newer systems will allow customization of pressure programs) 4. Open the arterial transducer to air, and zero both channels 1 and 2 on the hemodynamic system. Keep the arterial transducer open until completion of step 7. 5. On the RADI Analyzer, select REF OUT, then ALL REF OUT. Select 0, then 200 mmHg, verifying that the values are equal on both the RADI Analyzer and the cath lab hemodynamic system. Press the Escape key. 6. On the RADI Analyzer, select CAL, then CAL Pa Catheter. Press and hold the enter key for 3 seconds. The display should read Calibrating, then CAL OK. 7. The physician or scrub assistant should flush the PressureWire in the plastic loop holder or remove from the loop and place the distal guidewire tip in a syringe of sterile flush solution, laying the wire flat in the sterile field. Select CAL Pd Wire. Press and hold the enter key for 3 seconds. The display will read Calibrating, then CAL OK. The arterial transducer may now be closed to air. Prior to crossing the lesion, with the entire radiopaque segment outside the distal tip of the guide catheter inside the vessel, press and hold the EQUALIZE button for 3 seconds. The guide catheter and PressureWire waveforms should become superimposed on each other. 8. Administer the hyperemic agent of choice. For IC injections, rapidly inject the medication through the guiding catheter and immediately follow with a rapid injection of flush. Press the RECORD key, and the FFR is automatically calculated and displayed continuously while recording. Press the STOP/VIEW key when the pressure values begin to rise. The complete recording is displayed as time condensed, with a scrollable cursor at the lowest measured FFR. Record the IV administration for the entire duration of the infusion. Volcano Therapeutics, Inc. WaveMap/WaveWire/SmartWire System. As with the RADI system, the distal, sterile component is the guidewire, which is similar to a conventional interventional guidewire with the exception of a micro pressure transducer, 3 cm proximal to the distal tip at the transition of the radiopaque and radiolucent segments. Volcano Therapeutics, Inc. currently has two different pressure wires available: the WaveWire and the SmartWire. The WaveWire and SmartWire are only available in a length of 175 cm, but are compatible with the Cordis Cinch Extension Wire, allowing them to be extended to 300 cm. An adapter cable connects the WaveWire/SmartWire to the WaveMap during pressure measurements, and can be disengaged during wire placement and manipulation. The WaveMap is a portable computer system that is mounted on an IV pole and interfaces with the cath lab hemodynamic system (Figure 10-7). The WaveMap collects and interprets the signals sent by the guidewire micromanometer and displays the numeric values of both the guide catheter and the WaveWire/SmartWire. Phasic and mean waveforms of both are displayed on the cath lab hemodynamic system only. The patient should be heparinized per institutional protocol prior to inserting the WaveWire. The following steps may be used as a quick setup, and may vary depending on the hemodynamic system. 1. Plug in and turn on the WaveMap system. 2. Connect pressure inputs and outputs. The Pressure Interface Cable connects into the pressure channel 2 input of the hemodynamic system. The Pressure Input Cable connects to an output jack for pressure channel 1 of the hemodynamic system. 3. Select a cath lab hemodynamic system program that will allow display of two separate channels with both phasic and mean waveforms on a 200 mmHg scale (most newer systems will allow customization of pressure programs). 4. Open the arterial transducer to air, and zero both channels 1 and 2 on the hemodynamic system. Keep the arterial transducer open until completion of step 5. 5. Plug the WaveWire/SmartWire cable adapter into the WaveMap system; The physician or scrub assistant should flush the WaveWire in the plastic loop holder or remove from the loop and place the distal guidewire tip in a syringe of sterile flush solution, laying the wire flat in the sterile field. Press and hold the ZERO button and conflrm that the DMAP digital display reads 0 or Cost and Other Considerations Guidewire-based physiologic lesion assessment can be performed with relative ease in any cardiac catheterization laboratory without adding significant time to the procedure. Although the transducer or crystal elements in the Doppler and pressure measurement systems are somewhat fragile and can be damaged with rough handling, patient complications are no different from those encountered using routine interventional guidewires. Doppler FloMaps, WaveMaps and RADI Analyzers are all capital equipment costs, but the expenses may be minimized through leasing or special contractual agreements for wires. Doppler FloWires, WaveWires and PressureWires may range in price from $400“$600 each in the United States, depending on the hospital’s purchase agreement. The question really is: How necessary or valuable are physiologic measurements? FFR and CFR are tools with which the effectiveness of every interventional cardiology procedure can potentially be improved, but does that mean they should be used during every intervention? Physiologic measurements can be most cost-effective in the assessment of angiographic

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