Selective coronary angiography is one of the most commonly performed procedures in the United States. Cardiologists who perform coronary angiography must be capable of promptly recognizing abnormalities in pressure waveforms sampled from the catheter tip during selective coronary angiography. This is crucial for patient safety, proper diagnosis, and appropriate intervention. In addition, it is important for cardiologists to understand the more sophisticated coronary hemodynamic assessments that allow an invasive assessment of coronary physiology. These techniques serve as important adjuncts to angiography and have become indispensable to the routine practice of interventional cardiology.
Coronary Catheter Pressure Waveforms
Analysis of the pressure waveforms generated from the tip of the catheter during the performance of selective coronary angiography can provide valuable information to the operator. On engagement of a catheter into the ostium of either the right or left coronary artery, the physician should immediately review the catheter-tip pressure tracing before proceeding with contrast injection. This tracing normally appears as a typical aortic pressure waveform. An alert angiographer seeks two abnormalities in the pressure waveform: damping and ventricularization. Recognizing these abnormalities is essential, enhances the information provided by the angiogram, and may help avoid potentially serious complications of selective angiography.
Pressure damping refers to a drop in both the systolic and diastolic pressures with a loss of the usual features of an arterial pressure waveform. Damping of the waveform often indicates a narrowing of the coronary ostium. An example of this phenomenon is shown in Fig. 14.1 . In this case the catheter pressure showed marked damping on the engagement of the left coronary artery ( Fig. 14.1A ). The angiogram showed modest narrowing of the ostium of the left main stem ( Fig. 14.1B ). Removal of the catheter from the left main stem reestablished the normal aortic pressure ( Fig. 14.1C ).
Ventricularization of the catheter-tip pressure is seen when the diastolic pressure drops on the engagement of the catheter and shifts appearance from the usual arterial waveform to one with a ventricular waveform morphology ( Fig. 14.2 ). Pure ventricularization, in which there is only a drop in diastolic pressure and not in systolic pressure, implies a precise match between the diameters of the artery and the catheter lumen that leads to a coronary artery “wedge” pressure, reflecting left ventricular pressure ( Fig. 14.3 ). More typically, the pressure trace appears both ventricularized and damped (see Fig. 14.2 ). Both ventricularization and/or damping may be obvious; sometimes the change is subtle ( Fig. 14.4 ).
Both damping and ventricularization have similar causes ( Box 14.1 ); both imply that the catheter tip plugs and obstructs the coronary artery lumen. The most common causes are the presence of obstructive disease at the coronary ostium and selective engagement of a smaller artery, such as the conus branch of the right coronary artery. On observing these abnormal waveforms, the angiographer should determine the cause before proceeding with coronary arteriography in the usual manner. Ventricularization or damping of the catheter pressure waveform may be the only clue to the existence of a significant ostial stenosis not appreciated by angiography. More importantly, the injection of contrast into a catheter with a damped or ventricularized pressure tracing might result in serious complications. For instance, selective and forceful injection of a full syringe of contrast into a conus branch of the right coronary artery or a small nondominant artery may lead to ventricular fibrillation or asystole. Similarly, if damping or ventricularization is caused by the presence of a small caliber coronary artery, then the naive angiographer might inject excessive contrast, causing an arrhythmia. Furthermore, if significant atherosclerotic disease is present at the ostium, a carelessly performed contrast injection into a damped catheter could cause hydraulic dissection of the proximal artery and result in abrupt closure of the vessel, with potentially serious or even fatal consequences. In the event that damping is caused by the presence of air or thrombus in the catheter, an operator unaware of this finding might inadvertently inject these into the artery causing distal embolization and ischemic complications. Thus the angiographer should be constantly vigilant for these abnormal pressure waveforms.
During the Engagement of the Right Coronary Artery
- 1.
Atherosclerotic disease of the ostium of the RCA
- 2.
Catheter-induced spasm of the coronary artery
- 3.
Selective engagement of the conus branch of the RCA
- 4.
Total occlusion of the RCA
- 5.
Engagement of a small, nondominant artery
During the Engagement of the Left Coronary Artery
Atherosclerotic disease of the ostium of the left main stem
Deep seating of the catheter and selective engagement of either the LAD or LCX
During the Engagement of Either Coronary Artery
Presence of a small caliber artery with match in size between the diameter of the catheter and the coronary artery
Kinking of the catheter during catheter manipulation
Malposition of the catheter against the wall of the aorta
Presence of thrombus or air bubble in the catheter
When damping or ventricularization of the catheter pressure waveform is observed, the catheter may first be withdrawn into the aortic root and contrast injected into the aortic cusp to determine the presence of ostial disease. Alternatively, a very small amount of contrast may be gently injected into the damped coronary catheter to determine the cause. If coronary ostial spasm is suspected, administration of intraarterial or sublingual nitroglycerin can lead to improvement in the spasm and normalize the waveform and hemodynamics. Should an air or thrombus be suspected in the catheter system, the system should be aspirated and thoroughly cleared before the catheter is reengaged and an injection is performed.
Coronary Hemodynamics
Although coronary angiography forms the basis for revascularization decisions in patients with coronary artery disease, there are limitations to this method that may impair its utility in the diagnosis of ischemic syndromes. Coronary angiography provides purely anatomic information and high-resolution, two-dimensional images of the arterial lumen but does not provide any functional or physiologic information regarding the hemodynamic impact of a coronary lesion seen on angiography. Furthermore, angiography is influenced by injection technique, the patient’s body habitus, the presence of overlapping vessel segments, and arterial tortuosity. Coronary angiography is most helpful when the angiogram reveals either normal arteries or the presence of a severely stenotic lesion. However, it is not uncommon that a clinician is left with questions regarding the significance of findings seen on angiography. Particularly troublesome scenarios include eccentric lesions, diffuse disease, or lesions of intermediate stenosis severity (40%–70% narrowing). Sophisticated coronary hemodynamic measurements are possible and allow precise flow and pressure assessments in the coronary arteries. Adjunctive diagnostic testing provided by coronary hemodynamic assessment helps determine the physiologic significance of ambiguous lesions seen on angiography and can guide revascularization decisions.
Coronary Physiology
An increase in myocardial oxygen demand, caused by an increase in wall tension, contractility, or heart rate, requires an increase in oxygen supply or else results in myocardial ischemia. Since myocardial oxygen extraction from blood is already near maximal, the only significant mechanism to satisfy an increase in oxygen demand is to increase coronary blood flow to the myocardium. Coronary blood flow is regulated by changes in coronary vascular resistance. The epicardial coronary arteries function primarily as conductance vessels, accounting for only 5% of total coronary vascular resistance; the remaining 95% of resistance across the coronary bed is provided by the small (<300 μm) intramyocardial arterioles, and thus these are the major regulators of coronary blood flow.
These small resistance vessels are influenced by multiple regulators, including endothelium-derived agents (nitrous oxide, endothelin-dependent hyperpolarizing factor, prostacyclin, and endothelin), metabolites (adenosine, hypoxia, hypercapnia, and acidosis) and neurohormonal mechanisms. The process of autoregulation provides fine control of the resistance vessels, maintaining myocardial blood flow over the relatively wide range of coronary perfusion pressures seen with physiologic changes in blood pressure. Thus in normal individuals myocardial perfusion is maintained when the mean aortic pressure is between 50 and 150 mm Hg. Outside of this range, however, autoregulatory mechanisms fail, and coronary blood flow depends on perfusion pressure ( Fig. 14.5 ).
Effects of Coronary Stenosis on Coronary Flow
Resting blood flow in the left and right coronary arteries under normal conditions averages 0.5 to 1.0 mL/min/g and 0.3 to 0.6 mL/min/g, respectively. In the absence of a stenosis, coronary blood flow can increase four to five times above resting flow under conditions of high myocardial oxygen demand ( Fig. 14.6 ). This ability to increase blood flow over the resting state is termed coronary flow reserve . In the presence of a stenosis, a pressure drop will occur in a coronary artery; however, autoregulation will attempt to preserve blood flow by reducing the resistance of the small arterioles. Resting myocardial blood flow can be maintained over a wide range of stenosis. Eventually, when stenosis is severe, autoregulatory mechanisms become exhausted, and myocardial blood flow decreases. During conditions of increased myocardial oxygen demand, however, autoregulatory mechanisms fail at much lower stenosis severity. Accordingly, coronary flow reserve diminishes at less severe degrees of stenosis than resting coronary blood flow. Therefore a deficiency of coronary flow reserve implies maximal vasodilation of the resistance vessels and the presence of hemodynamically significant stenosis.
Coronary Flow Reserve
Several different terms describe different aspects of coronary flow reserve. Absolute flow reserve describes the ratio of hyperemic flow in a stenotic artery to resting flow in the same artery. This is the basis of the Doppler-derived method for invasively determining coronary flow reserve. Relative flow reserve is the term used to describe the ratio of hyperemic flow in a stenotic artery to hyperemic flow in a normal artery. This is the primary principle on which most noninvasive nuclear perfusion imaging techniques are based. Importantly, relative flow reserve depends on at least one normal vascular territory; therefore these techniques may be limited in the presence of multivessel coronary disease. Finally, fractional flow reserve (FFR) is the term used to describe the ratio of the maximum achievable flow in the presence of a stenosis to the theoretical maximum flow in the same vessel in the absence of a stenosis.
Doppler-Derived Absolute Flow Reserve
A 0.014-inch angioplasty guidewire outfitted with an ultrasound crystal at the tip, capable of generating a Doppler signal and measuring blood flow velocity, provides the means to estimate absolute flow reserve in the cardiac catheterization laboratory ( Fig. 14.7 ). This method assumes that blood velocity is proportional to blood flow for a constant vessel area. The technique involves positioning the tip of the Doppler wire past the stenosis and obtaining a satisfactory velocity envelope. The wire tip samples blood velocity a few millimeters away from the tip, typically expressed as the average peak velocity (APV). Normal resting APV is 15 to 30 cm/s. Without moving the wire tip, hyperemia is induced either from intravenous administration of adenosine (140 μg/kg per min for at least 2–4 min) or from intracoronary administration of bolus adenosine (20–100 μg bolus). The APV measurement is repeated during peak hyperemia. Coronary flow reserve (or more accurately coronary velocity reserve) is described as the ratio of hyperemic APV to resting APV. Normal coronary velocity reserve is at least 2.0, and values up to 5.0 may be observed. In the setting of moderate stenosis, coronary flow reserve <2.0 by the Doppler technique correlates with ischemia by nuclear perfusion techniques. The Doppler method is rarely used in the current era for clinical purposes, mainly because of several important limitations. This methodology is dependent on obtaining a stable, high-quality Doppler signal, which is not always feasible, particularly in the presence of vessel tortuosity or large branches. Intermittent loss of signal because of tenuous wire position against the wall of the artery may frustrate the operator. More importantly, however, the APV varies with blood pressure and heart rate and changes in these variables during the measurements influence the results. In addition, conditions other than the status of the epicardial coronary artery can cause abnormalities in the Doppler-derived coronary flow reserve. A failure to increase the APV in response to adenosine may be due to an unresponsive microvasculature rather than the presence of a significant stenosis. Conditions associated with high resting velocities (i.e., left ventricular hypertrophy) will not augment flow further with adenosine. This makes the technique less useful to assess the hemodynamic significance of a stenosis in the presence of conditions associated with microvascular abnormalities, such as a previous myocardial infarction, heart failure, left ventricular hypertrophy, and, perhaps, diabetes mellitus.
Thermodilution-Derived Absolute Flow and Absolute Flow Reserve
Thermodilution-derived methods of measuring absolute flow and flow reserve overcome some of the shortcomings of Doppler-derived absolute flow reserve. Advances in catheter and wire technology have allowed for the collection of thermodilution data using intracoronary saline at room temperature. The continuous infusion of room-temperature saline induces maximal hyperemia, which allows for direct quantification of absolute coronary flow and resistance. This method has been shown to be reliable, reproducible, operator independent, and does not require the administration of adenosine. Thermodilution flow reserve methodology has also been used to calculate coronary resistance, described by the index of coronary microvascular resistance or IMR. IMR values >40 are considered elevated and predict the incidence of 30-day major adverse cardiac events, infarction size, and the degree of microvascular obstruction in patients undergoing percutaneous coronary intervention (PCI). Specific details regarding thermodilution methods have been reviewed elsewhere. The thermodilution methods are primarily used as research tools and have not been embraced clinically.
Pressure-Derived Fractional Flow Reserve
FFR is an alternative method of assessing the hemodynamic significance of an intermediate or ambiguous coronary stenosis. This popular technique is simple to perform and is based on the measurement of the coronary pressure, using an angioplasty guidewire outfitted with a micromanometer. The mathematics and experimental basis of this technique have been described. The underlying concept states that FFR is the ratio between the maximum achievable blood flow in the presence of a stenosis and the theoretical maximum flow in the absence of a stenosis (i.e., a normal artery). It can be calculated simply by using the formula:
The unequivocal normal value is 1.0.
The derivation of this formula is simple ( Fig. 14.8 ). Based on Ohm’s law, coronary flow is equal to the coronary driving pressure divided by coronary resistance. Coronary driving pressure can be expressed as the difference between coronary artery pressure and coronary venous pressure (P v ), with P v best approximated by the right atrial pressure. In the absence of a coronary stenosis, the coronary driving pressure equals the difference between the aortic pressure (P a ) and P v . Thus flow in the absence of a stenosis is simply (P a − P v )/Resistance 1. Similarly, in the presence of a coronary stenosis, the coronary driving pressure equals the difference between the pressure distal to the stenosis (Pd) and P v , with flow in the presence of a stenosis expressed as (Pd − P v )/Resistance 2. FFR is the ratio of maximum flow in the presence of a stenosis to the theoretical maximum flow if the artery were normal. Therefore the formula becomes:
During maximum hyperemia, because the resistances R 1 and R 2 are very low, they will be similar and cancel out. In addition, P v is usually very low, does not contribute significantly, and is usually eliminated from the calculation. The formula becomes simplified as:
Although the normal value of 1.0 is well accepted and has been firmly established in humans, the value below which a stenosis is deemed significant is of some debate. Several investigations have determined the FFR value associated with ischemia on noninvasive tests. These investigations involved patients with single vessel disease, stable chest pain syndromes, and moderate coronary lesions and excluded patients with potentially confounding conditions such as left ventricular hypertrophy or prior myocardial infarction. Based on these studies, lesions associated with ischemia have an FFR of <0.75. In one of the original validation studies of FFR (using an FFR cutoff of <0.75 as significant) against noninvasive ischemic testing, the sensitivity of FFR in the identification of reversible ischemia was 88%, the specificity 100%, the positive predictive value 100%, the negative predictive value 88%, and the accuracy 93% . Lesions with an FFR between 0.75 and 0.80 are generally recognized as borderline and may, in fact, represent significant lesions, particularly in the setting of left ventricular hypertrophy or high right atrial pressure. In these borderline or greyzone cases, the decision whether or not to revascularize was typically left to the discretion of the operator. However, studies show a gradient of risk within the borderzone values and currently, it is generally accepted to revascularize lesions with an FFR of <0.80 to allow for error and account for the chance that these borderline values may be ischemic. This cutoff value has served as the basis of many important large-scale clinical trials using FFR for revascularization decisions.
Fractional Flow Reserve Technique
Assessment of FFR is fairly straightforward to perform, using basic interventional skills ( Fig. 14.9 ). After engaging a standard angioplasty guide catheter into the coronary ostium, the pressure wire is zeroed and calibrated. Because the procedure involves instrumentation of the coronary artery, the University of Virginia Cardiac Catheterization Laboratory (Charlottesville, Virginia) typically administers an intravenous bolus of unfractionated heparin (50 U/kg) before wire passage distal to the coronary lesion to prevent catheter and wire thrombosis. Once the operator has established that the pressures recorded from the catheter tip and the pressure wire’s micromanometer are identical ( Fig. 14.9B and C ), the wire is advanced down the coronary artery and the transducer positioned several millimeters distal to the lesion in question. The pressure waveforms are recorded at rest and during maximal hyperemia induced by one of several methods. Intracoronary adenosine is perhaps the simplest method. During the early trials and clinical experiences with FFR, clinicians typically used 12 to 40 μg injected as a bolus into the right coronary artery and 16 to 60 μg into the left coronary artery using a concentration of 10 μg/mL. Additional studies learned that higher doses are necessary to achieve maximal hyperemia with doses of up to 600 μg needed to achieve the maximal hyperemia observed with an intravenous infusion of adenosine. Side effects, such as transient high-grade atrioventricular block, bradycardia, and asystole, become more common with high-dose intracoronary bolus injections. Thus the optimal intracoronary dose balances adequate hyperemia with minimal side effects. A study by Adjedj et al. found that the optimal dose was 100 μg for the right coronary artery and 200 μg for the left coronary artery to provide an FFR value within 0.01 of the value associated with maximal hyperemia and with minimal side effects. To capture maximal hyperemia, simultaneous catheter tip (or P a ) and distal wire pressure (P d ) are recorded for 15 to 20 seconds. The point of maximum hyperemia is apparent at the nadir of the mean pressure typically observed 10 to 30 seconds after the bolus is administered.
An infusion of adenosine through a large peripheral vein at 140 μg/kg/min is an alternative and commonly used method of achieving hyperemia. Intravenous administration provides a longer period of hyperemia and a more stable response, but at a greater cost and more potential for systemic side effects such as flushing, dyspnea, hypotension, and chest pain. Adenosine is contraindicated in patients with active bronchospasm and should be used with caution in those with obstructive lung disease. Using this methodology, hyperemia is usually maximal 1 to 2 minutes into the peripheral infusion. Because of the short half-life of adenosine, it was believed that intravenous infusions should be administered through a large central vein such as the femoral vein; however, it appears that hand-vein infusion of adenosine results in the same FFR values as central femoral-vein infusion. Again, similar to the intracoronary bolus of adenosine, the point of maximum hyperemia with intravenous infusion is at the nadir of the mean pressure typically observed 1 to 2 minutes after the start of the infusion. Fluctuations in the extent of hyperemia during the course of the infusion are sometimes observed. The mechanism of these fluctuations is not entirely clear and may represent a compensatory response to hyperemic flow. If observed, the “true” FFR is the lowest value observed.
Regardless of the method used to achieve hyperemia, the pressure waves are recorded during maximal hyperemia, and FFR is simply calculated as P d /P a , as described above ( Fig. 14.9D ). Most operators end the procedure by withdrawing the pressure transducer to the catheter tip, verifying that the pressures remain equal, and confirming that transducer drift has not occurred, establishing the reliability of the measurements.
Several important considerations and potential sources of errors when making these measurements include the following:
- 1.
The operator should be careful to note if the engagement of the guide catheter causes pressure damping or ventricularization. This will falsely lower the P a and cause an erroneously high calculated FFR ( Fig. 14.10 ). Furthermore, if the intracoronary method of adenosine administration is used, the operator should avoid using a guide catheter with side holes and be sure the catheter is selectively engaged in the artery. This ensures that the adenosine bolus actually enters the coronary circulation; otherwise, maximal hyperemia will not occur, underestimating the FFR.
Fig. 14.10
Example of a potential source of error during fractional flow reserve measurement. (A) There is subtle ventricularization of the guide catheter pressure waveform, resulting in a falsely low aortic pressure (74 mm Hg) with a mean coronary pressure distal to the stenosis of 68 mm Hg and a calculated fractional flow reserve of 0.92, suggesting that this lesion is not significant. (B) However, when the guide catheter is repositioned into the aorta, the mean aortic pressure rises to 86 mm Hg with a mean coronary pressure distal to the stenosis of 64 mm Hg and a calculated fractional flow reserve of 0.75, suggesting that the lesion is, in fact, a significant one.
- 2.
If the FFR value obtained with intracoronary adenosine is in the borderline range (i.e., 0.80–0.81), the operator might consider repeating the measurement at higher bolus doses of adenosine (up to 600 μg) or switch to intravenous adenosine before concluding that the lesion is not hemodynamically significant.
- 3.
Operators should be aware that theophylline and related drugs block adenosine’s activity and may blunt the hyperemic response, falsely elevating the FFR. Patients should hold these medications for at least 12 hours to avoid this pitfall. One cup of coffee more than 1 hour before adenosine administration does not interfere with measurements.
- 4.
A point often not considered relates to the potential risk of guidewire instrumentation of an atherosclerotic coronary artery. Rarely, the guidewire passage disrupts or dissects the atherosclerotic plaque and causes abrupt vessel closure. Therefore if the lesion in question is not amenable to percutaneous interventional techniques, FFR should not be performed.
- 5.
Finally, transducer pressure drift can occur during the performance of the procedure. For this reason, confirmation that the catheter-tip pressure and the pressure wire transducers are the same at the conclusion of the case provides the operator with greater confidence in the FFR measurement obtained.
Clinical Applications and Prognostic Value of Fractional Flow Reserve
Coronary hemodynamic assessment is indispensable in the current practice of interventional cardiology. FFR is most commonly used to assess lesions that appear only modestly stenotic. Angiography alone is notoriously misleading in this subset. In fact, even experienced interventional cardiologists are often unable to discriminate significantly from nonflow limiting lesions by angiography alone, and they often disagree regarding the significance of the same lesions! In general, when a cardiologist stares at an angiogram over and over again, scratches their head and requests multiple additional views, and still remains unsure, it is time to perform FFR.
Fig. 14.11 is an example of the utility of FFR in a 52-year-old female with peripheral vascular disease and a remote history of a coronary intervention on the right coronary artery, now presenting with an anginal chest pain syndrome. Angiography revealed total occlusion of a small right coronary artery and normal-appearing left main and left circumflex (LCX) arteries. The left anterior descending (LAD) artery had a stenosis of moderate severity at the bifurcation of a diagonal branch ( Fig. 14.11A ). Despite imaging in multiple views, the lesion did not appear particularly worrisome or severe. However, FFR assessment demonstrated that this lesion was hemodynamically significant with an FFR calculated at 0.71 ( Fig. 14.11B ).
Another common indication for FFR is the assessment of ambiguous lesions, that is, coronary disease not well visualized by angiography either because of overlapping segments, vessel tortuosity, or lesion eccentricity. FFR assessment is especially valuable when the patient’s clinical symptoms are atypical. The FFR measurement can be extremely valuable to the cardiologist who wishes to reconcile the clinical syndrome with the angiogram. If the ambiguous lesion is not significant, it is unlikely that the patient’s atypical symptoms are because of the stenosis or that the condition will improve with revascularization. Alternatively, the angiogram may underrepresent an important stenosis, causing the practitioner to erroneously dismiss the symptoms as noncardiac.
The angiogram shown in Fig. 14.12 reveals an ambiguous lesion in the proximal LAD artery in a 55-year-old morbidly obese female with dyspnea on exertion and an abnormal, but nondiagnostic, noninvasive study. Left ventricular function was normal, and no atherosclerotic disease was found in the right coronary and circumflex arteries. In this case a complex array of branches emanated from the proximal segment of the LAD artery, overlapping the area in question. In addition, the patient’s body habitus limited the range of angiographic angles, preventing optimal visualization of the area. An FFR of 0.94 confirmed that this lesion was not significant and, therefore, not responsible for the clinical syndrome.
