Author's Accepted Manuscript
Assessment of Coronary Blood Flow in the Cardiac Catheterization Laboratory John E.A. Blair MD, FACC, Mark J. Ricciardi MD, FACC
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S0146-2806(14)00013-9 http://dx.doi.org/10.1016/j.cpcardiol.2014.02.002 YMCD271
To appear in:
Curr Probl Cardiol
Cite this article as: John E.A. Blair MD, FACC, Mark J. Ricciardi MD, FACC, Assessment of Coronary Blood Flow in the Cardiac Catheterization Laboratory, Curr Probl Cardiol, http://dx.doi.org/10.1016/j.cpcardiol.2014.02.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Assessment of Coronary Blood Flow in the Cardiac Catheterization Laboratory
John E. A. Blair, MD, FACC; Mark J. Ricciardi, MD, FACC
Cardiology Division, Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine
Corresponding Author: Mark J. Ricciardi, MD Director, Cardiac Catheterization and Interventional Cardiology Northwestern Bluhm Cardiovascular Institute 676 North St Clair, Suite 600 Chicago, IL 60611 312.926.2826
[email protected]
Disclosure Statement: The authors have no financial associations that might pose a conflict of interest in connection with submitted article.
Letters of permission: Figure permission letters were applied for and are pending.
Dr John E. A. Blair biosketch: Dr. Blair is a fellow in interventional cardiology at Northwestern University Feinberg School of Medicine / Northwestern Bluhm Cardiovascular Institute. He received his medical degree and completed internal medicine residency at the University of Chicago Pritzker School of Medicine followed by cardiovascular disease fellowship at Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital. He then spent four years as a general cardiologist and Air Force officer at the San Antonio Military Medical Center, where he served on the faculty at the joint Army/Air Force cardiology fellowship program. He is board certified in Cardiovascular Disease and fellow of the American College of Cardiology (FACC). His interests are patient care and research centering on heart failure, hemodynamics, and coronary artery disease. Dr Mark J. Ricciardi biosketch: Dr. Ricciardi is the Director of the Cardiac Catheterization Center and Interventional Cardiology at Northwestern Memorial Hospital and the Northwestern Bluhm Cardiovascular Institute. He received his medical degree from New York University, completed internal medicine residency at Yale, and cardiovascular and interventional cardiology fellowship at the University of Michigan. He is board certified in Interventional Cardiology and Cardiovascular Medicine. Dr. Ricciardi is an active member and fellow of the American Heart Association (FAHA), the American College of Cardiology (FACC) and the Society for Cardiovascular Angiography and Intervention (FSCAI). His interests are patient care, research and education centering on complex coronary, structural heart, and heart valve interventions.
Table of Contents 1. Introduction 2. Basic coronary physiology 3. Measurement of coronary blood flow 4. Coronary flow assessment in select patient populations 5. Conclusions
Abstract Coronary blood flow is tightly autoregulated but is subject to epicardial and microvascular obstruction, primarily due to coronary atherosclerosis. Because coronary flow limitation underlies ischemic heart disease, an understanding of coronary physiology is paramount. Measurement of coronary blood flow, once relegated to the research laboratory is now easily performed in the cardiac catheterization laboratory. In particular, the measurement of fractional flow reserve has been extensively studied and is an important adjunct to clinical decision-making. Measurement of coronary flow informs clinicians of prognosis, guides revascularization therapy, and forms the basis of ongoing research in treatment of complex myocardial disease processes. Newer methods of assessing coronary flow measurements are undergoing validation for clinical use and should further enhance our ability to assess the importance of coronary flow in clinical disease.
1. Introduction Fundamental concepts in coronary blood flow, once a subject of basic research, has helped to inform important decisions in the treatment of coronary artery disease. While providing useful information about lesion severity and morphology, the anatomic information garnered by performing coronary angiography and intravascular ultrasound may not always correlate with myocardial ischemia. It has been known for some time that complementary intra-procedural assessment of coronary physiology would provide meaningful information for the treatment of coronary artery disease. As technology has improved, measurement of blood flow has evolved to the point where intracoronary guidewire-based measurement of pressure and flow can be performed easily and safely. In this paper, we will review underlying concepts of coronary physiology, the development and theory behind measurement of coronary flow, and clinical applications of these measurements.
2. Basic Coronary Physiology Myocardial blood flow is determined by the balance of myocardial oxygen (MVO2) demand and supply. As MVO2 demand increases, coronary blood flow increases to meet this demand. Since the heart relies almost entirely on instantaneous oxidation of substrates such as free fatty acids, glucose, lactate, pyruvate, and amino acids to form high-energy phosphates for consumption by the myocardium, there is little room to accumulate oxygen debt as seen in skeletal muscle.1 Any compromise in substrate availability results in conservation of energy for the maintenance of cellular function rather than mechanical work, resulting in myocardial “hibernation” or infarction, depending on the time course of such compromise.2
At resting state, basal cellular metabolism accounts for only 20% of myocardial cellular energy use, while myocardial force generation (and to a lesser degree relaxation and electrical activity) accounts for the remaining 80%. Thus, MVO2 is closely related to the
energy it requires for myocardial force generation. This energy requirement is related to four variables: cardiac myocyte shortening and contractility, myocardial wall tension, and heart rate; the latter being the largest contributor.2-4 With exercise or physiological stress, MVO2 demand is met primarily by increases in coronary blood flow, while changes in minute ventilation, pulmonary capillary transit of oxygen, and hemoglobin transport of oxygen play minor roles.
David P. Faxon, MD: The degree of coronary obstruction is the primary determinant of myocardial ischemia but other factors are important as well. As mentioned, coronary blood flow is highly auto-regulated in patients without coronary disease, but in the setting of symptomatic coronary artery disease even in the absence of a significant stenosis, autoregulation is often impaired. Those with a diminished autoregulation have a poor long-term mortality in both patients with a myocardial infarction or stable angina. (van de Hoef et al Circ Cardiovasc Int 2013;6:207-15, van de Hoef et al Circ Cardiovascular Int 2013;6:329-335)
Conversely, the presence of coronary collaterals can significantly attenuate the degree of ischemia and improve outcome. The presence and degree of collaterals is variable but they are usually present when a severe stenosis chronically limits resting blood flow. Collaterals can reduce myocardial ischemia, ECG changes associated with ischemia, symptoms and in a large meta-analysis have been shown to reduce long term mortality. (Seiler Circ Cardiovasc Inter 2013;6: 719-728, Meier EHJ 2012;33:614-621))
Coronary blood flow is inversely related to coronary resistance. Coronary resistance is the sum of epicardial, precapillary arteriolar, and myocardial capillary resistances.2,5 Normal, non-diseased epicardial vessels are direct conduits and provide no resistance to blood flow. Precapillary arterioles connect the epicardial arteries to the myocardial capillaries and are the primary determinants of coronary resistance and flow. Smooth
muscle in the arterioles dilate and constrict to adjust to blood pressure over the range of 60-180 mmHg. The myocardial capillary bed forms an extensive network connecting each myocyte, often referred to as the microvasculature.
Coronary flow reserve (CFR) is the ability of the coronary circulation to augment coronary flow from a basal state to maximum hyperemia in response to physiologic or pathologic stimuli. It is expressed as the ratio of maximum hyperemic flow to resting flow and ranges from 2-5 in humans.2-4,6 Experimental animal studies have demonstrated that increasing epicardial stenoses beyond 60% diameter produces a gradual decline in maximal coronary flow, while stenoses beyond 80% impairs resting blood flow.7
3. Measurement of Coronary Blood Flow Human studies dating back 30 years have shown poor correlation with angiographic degree of stenosis and coronary blood flow. A study of 39 subjects undergoing coronary arterial bypass surgery demonstrated a very weak inverse correlation between angiographic stenosis severity and CFR (r = -0.25) despite good inter- and intra-observer agreement of angiographic severity.8 Even computer-based quantitative coronary angiography resulted in poor correlation of physiologic ischemia.9 The reason for this discrepancy is at least partially due to the multiple lesion characteristics that factor into physiologic significance, including minimal luminal dimensions and area, stenosis length, exit and entrance angles, reference vessel diameter, and diffuse coronary narrowing. Even after accounting for these parameters with intravascular ultrasound (IVUS), there still is disagreement between anatomic and physiologic assessment of lesion severity, which may be attributed to disease of the microvasculature.10 Physiologic assessment is therefore becoming the gold-standard for measurement of coronary stenosis severity in multiple clinical scenarios. Two methods of coronary physiologic assessment are relevant in clinical practice; angiographic flow estimation and direct intracoronary pressure and flow measurements. Other methods, like coronary sinus flow assessment,11,12 are beyond the scope of this review.
Angiographic Flow Estimation The Thrombolysis in Myocardial Infarction (TIMI) investigators developed several methods of estimating coronary blood flow using angiography. These qualitative and quantitative techniques have historically been studied in the setting of pharmacological and mechanical reperfusion therapies for acute myocardial infarction (AMI).
TIMI Flow Grade The simplest of methods to grade coronary flow rates is the TIMI flow grade, which is qualitatively assessed as contrast is injected into the artery of interest (Table 1).13 Normal TIMI 3 flow following pharmacological reperfusion therapy has been associated with improved outcomes, whereas lower TIMI flow grades have been associated with poorer outcomes.14
TIMI Frame Count A quantitative method of grading TIMI flow is the TIMI frame count (TFC), defined as the number of cine frames required for radiographic contrast to reach a standardized distal coronary landmark in the culprit vessel.15 The TFC can be further corrected by normalizing the TFC to the left anterior descending (LAD) coronary artery to obtain the corrected TFC (CTFC). (Since the LAD is longer than the other two epicardial arteries, the CTFC is calculated by dividing the TFC in the LAD by 1.7, a correction factor that normalizes the length of the LAD to the other two arteries.)15 The CTFC is a more precise measure of coronary flow than TIMI flow grades as evidenced by the fact that while normal CTFC is less than 20, CTFC of up to 40 is seen in TIMI 3 flow. Analysis of early thrombolytic trials demonstrated worse outcomes with CTFC >20 compared to normal CTFC, even if TIMI 3 flow is present (i.e. CTFC 20-40).16 Presence of high CTFC despite an open epicardial artery in the setting of AMI is thought to represent microvascular obstruction or dysfunction. The above methods are reproducible and have
minimal inter- and intra-observer variability, however injection rate and catheter lumen size may affect the frame counts by up to two frames.17
David P. Faxon, MD: Additional technical issues relate to the use of intracoronary bolus adenosine versus central venous or peripheral venous infusions. Studies have shown greater variability with intra-coronary bolus and peripheral venous administration. The current recommendations are for central venous infusion. (Jeremias et al Am Heart J 200;140:651-7) In addition administration of adenosine can result an initial greater coronary than peripheral vasodilatation resulting in falsely low FFR readings. It is recommended to wait until the pressure measurement stabilizes over a one minute before recording the FFR. (Tarkin et al Circ Cardiovasc Interv 2013;6:654-61)
TIMI Myocardial Perfusion Grade The TIMI myocardial perfusion grade (TMPG) is a semi quantitative assessment of myocardial perfusion originally developed by the Zwolle Myocardial Infarction Study Group in the Netherlands (Table 1).18 Unlike TIMI flow grade and CTFC, TMPG grades myocardial flow on the capillary level rather than on the epicardial vessel level. TMPG is assessed in the artery of interest by choosing the angiographic projection that best visualizes the supplied myocardium. Images are obtained with adequate injection allowing reflux of contrast into the aortic root. Injection is stopped after opacification of the coronary sinus, and cineangiography is continued until three cardiac cycles after myocardial blush begins to wash out. Low TMPG grade has been shown to be a poor predictor of outcomes after thrombolysis and percutaneous coronary intervention, despite the presence TIMI 3 flow, which indicates the importance of microvascular obstruction and dysfunction in this disease process.19,20
Wire-based Coronary Flow Measurements
Intracoronary guidewires engineered with pressure, Doppler, or temperature probes allow direct measurement of coronary pressure and flow. Such wire-based measurements are used to determine the significance of a coronary stenosis, assess the microvascular circulation, and gauge the physiologic response to mechanical or pharmacologic interventions.
The general technique is to place a 0.014” sensory angioplasty guide wire through a guide catheter into the coronary artery of interest after administration of intravenous heparin (40-60 Units per kilogram). Intracoronary nitroglycerin is often administered to maximally dilate the epicardial blood vessels. Once the wire is placed in the desired location, coronary hyperemia is pharmacologically induced by maximally dilating the resistance arterioles. This allows for the assessment of the epicardial vessel independent of the microvasculature. Intravenous adenosine is the most common agent used to induce hyperemia.21, 22
Direct Coronary Pressure Measurement – Fractional Flow Reserve Fractional Flow Reserve (FFR) is a lesion specific, physiologic index of the hemodynamic severity of intracoronary lesions and is the most commonly used invasive tool used to assess coronary flow. Its main strength is to identify lesions responsible for ischemia that in many cases would have been undetected or not correctly assessed by angiography alone.
FFR is defined as the ratio of the maximal flow to the myocardium in the presence of a coronary stenosis normalized to the theoretical maximal flow in the same artery without a stenosis. Normal FFR is 1.0 and suggests that flow in the distal vessel is normal; an FFR of 0.50 suggest half normal maximal flow in the distal vessel. FFR uses the principle of pressure loss: pressure distal to a significant stenosis is lost to friction, turbulence, and flow separation.23 The pressure gradient across a stenosis is related to flow in a curvilinear manner, allowing pressure to be used as a surrogate for flow in the calculation
of FFR.24 Experimentally-derived equations to determine FFR of the myocardium (FFRmyo), coronary artery (FFRcor), and collateral circulation (FFRcollateral) are as follows, where Pd, Pa, Pv, and Pw are the mean distal, aortic, venous, and wedge pressures:25,26 FFRmyo = (Pd –Pv) / (Pa – Pv) FFRcor = (Pd – Pw) / (Pa – Pw) FFRmyo= FFRcor + FFRcollateral In clinical practice, FFRmyo is used to determine FFR of the coronary territory of interest, and is simply the ratio of distal coronary to aortic pressure (Pd/Pa), assuming negligible contribution of Pv to the equation. Commercially available guidewires that contain a pressure sensor at the end of the radio-opaque portion of the wire allow for easy measurement of FFR.
David P. Faxon, MD: Coronary collateral flow is difficult to assess but can be estimated with PET imaging, contrast echo, angiography and by pressure or flow measurements. The most common method is to use pressure measurement and the following formula.
CFI = (Pocc – CVP)/Pa – CVP)
Where CFI is coronary flow index, Pocc is the pressure downstream from the occlusion, CVP is the central venous pressure and Pa is the mean aortic pressure. FFR takes into account collateral flow but by its self is not able to separate the component due to flow through the stenosis and flow from collateral flow. (Seiler Circ Cardiovasc Interv 2013;6:719-728)
Initial studies of FFR in humans demonstrated that FFR of 0.75 or less had very good sensitivity and specificity for detecting myocardial ischemia.27-29 Subsequent studies demonstrated a cutoff FFR of less than 0.80 to have better sensitivity, suggesting that FFR 95% reproducibility for determining whether lesions were ischemic when outside the FFR range of 0.75-0.85 (Figure 1). However, in the 0.77-0.83 FFR range reproducibility is diminished (there was only 50% reproducibility at FFR 0.80), implying that the biologic variability between measurements creates a “measurement gray zone”.31 David P. Faxon, MD: Other recognized limitations of FFR is the measurement of serial stenosis and stenosis involving bifurcations that are discussed later, Since FFR is dependent on the size of the myocardial perfusion bed, proximal stenosis are more likely to have a positive FFR than distal stenosis. Likewise in the presence of infarcted myocardium, the viable myocardial bed is smaller and FFR is higher. The FFR in this setting accurately reflects the degree of myocardial ischemia however. (Pijls J Am Coll Card 2012;59:1045-57) One additional situation that can lead to false FFR is in multi-vessel disease that involves major branches. For instance when there is an intermediate stenosis in the left main and a high-grade stenosis in the LAD, the FFR in the circumflex (reflecting the LM stenosis) will be falsely high (less significant) due to a significant reduction in the size of the myocardium served by the LM. (Yong et al Circ Cardiovasc Interv 2013;6:161-5)
One of the advantages of FFR stems from the real-time nature of Pd and Pa measurement making FFR independent of systemic blood pressure and heart rate.23 In addition, the measurement reflects the contribution of epicardial stenosis independent of the microvasculature of the supplied myocardium and can be reliably interpreted in multivessel disease, infracted myocardium, and areas with collaterals. Examples of FFR measurements are demonstrated in Figure 2.
FFR Limitations FFR operates under two assumptions that limit its applicability in some clinical situations. It assumes a linear relationship between pressure and flow, when in fact it is curvilinear.24,32 The use of the true FFRmyo equation may in part compensate for this, but it is too cumbersome to use in daily clinical practice. . In addition, FFR assumes minimal resistance from the microvasculature after peak vasodilation, an assumption that may break down in cases of left ventricular hypertrophy, conditions associated with extensive microvascular damage, or in high baseline flow states such as sepsis or liver disease.33 As with all clinical measurements, FFR may be limited if special care is not taken to ensure careful and accurate sampling. For example, inaccuracies in transducer “zeroing” and normalization of the proximal aortic pressure may dramatically alter the measured FFR ratio..34 Direct Coronary Flow Measurement – Coronary Flow Reserve Coronary flow reserve (CFR), also known as coronary vasodilatory reserve (CVR) or coronary flow velocity reserve, is no longer routinely used in clinical practice because of several limitations (see below) and the ascendance of more user-friendly FFR methods. CFR is defined as the ratio of maximal to basal coronary flow, and can be measured in an individual artery using Doppler or thermodilution methods. Normal CFR in humans exceeds 3.0, while a CFR of 0.80, as well as improvement in clinical outcomes when PCI is performed on top of optimal medical therapy in patients with FFR ≤ 0.80.
Multivessel Disease It has been long recognized that myocardial SPECT is limited in identification of multiple vascular territories affected by multivessel disease.52 In the era of bare-metal stents, a retrospective analysis 102 subjects with multivessel disease in which one artery was treated by PCI and at least one stenosis was deferred from PCI based on an FFR > 0.75 revealed low overall major adverse cardiac events (MACE, 9% and 13% at 12 and 36 months, respectively), with 6.3% related to one of the deferred vessels and 12.2% related to the initially treated artery.53 In addition, prospective, nonrandomized study of 137 consecutive subjects with multivessel disease who underwent FFR-guided PCI (n = 57) or conventional PCI (n = 80), with a cutoff FFR of
Assessment of Coronary Blood Flow in the Cardiac Catheterization Laboratory John E.A. Blair MD, FACC, Mark J. Ricciardi MD, FACC
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S0146-2806(14)00013-9 http://dx.doi.org/10.1016/j.cpcardiol.2014.02.002 YMCD271
To appear in:
Curr Probl Cardiol
Cite this article as: John E.A. Blair MD, FACC, Mark J. Ricciardi MD, FACC, Assessment of Coronary Blood Flow in the Cardiac Catheterization Laboratory, Curr Probl Cardiol, http://dx.doi.org/10.1016/j.cpcardiol.2014.02.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Assessment of Coronary Blood Flow in the Cardiac Catheterization Laboratory
John E. A. Blair, MD, FACC; Mark J. Ricciardi, MD, FACC
Cardiology Division, Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine
Corresponding Author: Mark J. Ricciardi, MD Director, Cardiac Catheterization and Interventional Cardiology Northwestern Bluhm Cardiovascular Institute 676 North St Clair, Suite 600 Chicago, IL 60611 312.926.2826
[email protected]
Disclosure Statement: The authors have no financial associations that might pose a conflict of interest in connection with submitted article.
Letters of permission: Figure permission letters were applied for and are pending.
Dr John E. A. Blair biosketch: Dr. Blair is a fellow in interventional cardiology at Northwestern University Feinberg School of Medicine / Northwestern Bluhm Cardiovascular Institute. He received his medical degree and completed internal medicine residency at the University of Chicago Pritzker School of Medicine followed by cardiovascular disease fellowship at Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital. He then spent four years as a general cardiologist and Air Force officer at the San Antonio Military Medical Center, where he served on the faculty at the joint Army/Air Force cardiology fellowship program. He is board certified in Cardiovascular Disease and fellow of the American College of Cardiology (FACC). His interests are patient care and research centering on heart failure, hemodynamics, and coronary artery disease. Dr Mark J. Ricciardi biosketch: Dr. Ricciardi is the Director of the Cardiac Catheterization Center and Interventional Cardiology at Northwestern Memorial Hospital and the Northwestern Bluhm Cardiovascular Institute. He received his medical degree from New York University, completed internal medicine residency at Yale, and cardiovascular and interventional cardiology fellowship at the University of Michigan. He is board certified in Interventional Cardiology and Cardiovascular Medicine. Dr. Ricciardi is an active member and fellow of the American Heart Association (FAHA), the American College of Cardiology (FACC) and the Society for Cardiovascular Angiography and Intervention (FSCAI). His interests are patient care, research and education centering on complex coronary, structural heart, and heart valve interventions.
Table of Contents 1. Introduction 2. Basic coronary physiology 3. Measurement of coronary blood flow 4. Coronary flow assessment in select patient populations 5. Conclusions
Abstract Coronary blood flow is tightly autoregulated but is subject to epicardial and microvascular obstruction, primarily due to coronary atherosclerosis. Because coronary flow limitation underlies ischemic heart disease, an understanding of coronary physiology is paramount. Measurement of coronary blood flow, once relegated to the research laboratory is now easily performed in the cardiac catheterization laboratory. In particular, the measurement of fractional flow reserve has been extensively studied and is an important adjunct to clinical decision-making. Measurement of coronary flow informs clinicians of prognosis, guides revascularization therapy, and forms the basis of ongoing research in treatment of complex myocardial disease processes. Newer methods of assessing coronary flow measurements are undergoing validation for clinical use and should further enhance our ability to assess the importance of coronary flow in clinical disease.
1. Introduction Fundamental concepts in coronary blood flow, once a subject of basic research, has helped to inform important decisions in the treatment of coronary artery disease. While providing useful information about lesion severity and morphology, the anatomic information garnered by performing coronary angiography and intravascular ultrasound may not always correlate with myocardial ischemia. It has been known for some time that complementary intra-procedural assessment of coronary physiology would provide meaningful information for the treatment of coronary artery disease. As technology has improved, measurement of blood flow has evolved to the point where intracoronary guidewire-based measurement of pressure and flow can be performed easily and safely. In this paper, we will review underlying concepts of coronary physiology, the development and theory behind measurement of coronary flow, and clinical applications of these measurements.
2. Basic Coronary Physiology Myocardial blood flow is determined by the balance of myocardial oxygen (MVO2) demand and supply. As MVO2 demand increases, coronary blood flow increases to meet this demand. Since the heart relies almost entirely on instantaneous oxidation of substrates such as free fatty acids, glucose, lactate, pyruvate, and amino acids to form high-energy phosphates for consumption by the myocardium, there is little room to accumulate oxygen debt as seen in skeletal muscle.1 Any compromise in substrate availability results in conservation of energy for the maintenance of cellular function rather than mechanical work, resulting in myocardial “hibernation” or infarction, depending on the time course of such compromise.2
At resting state, basal cellular metabolism accounts for only 20% of myocardial cellular energy use, while myocardial force generation (and to a lesser degree relaxation and electrical activity) accounts for the remaining 80%. Thus, MVO2 is closely related to the
energy it requires for myocardial force generation. This energy requirement is related to four variables: cardiac myocyte shortening and contractility, myocardial wall tension, and heart rate; the latter being the largest contributor.2-4 With exercise or physiological stress, MVO2 demand is met primarily by increases in coronary blood flow, while changes in minute ventilation, pulmonary capillary transit of oxygen, and hemoglobin transport of oxygen play minor roles.
David P. Faxon, MD: The degree of coronary obstruction is the primary determinant of myocardial ischemia but other factors are important as well. As mentioned, coronary blood flow is highly auto-regulated in patients without coronary disease, but in the setting of symptomatic coronary artery disease even in the absence of a significant stenosis, autoregulation is often impaired. Those with a diminished autoregulation have a poor long-term mortality in both patients with a myocardial infarction or stable angina. (van de Hoef et al Circ Cardiovasc Int 2013;6:207-15, van de Hoef et al Circ Cardiovascular Int 2013;6:329-335)
Conversely, the presence of coronary collaterals can significantly attenuate the degree of ischemia and improve outcome. The presence and degree of collaterals is variable but they are usually present when a severe stenosis chronically limits resting blood flow. Collaterals can reduce myocardial ischemia, ECG changes associated with ischemia, symptoms and in a large meta-analysis have been shown to reduce long term mortality. (Seiler Circ Cardiovasc Inter 2013;6: 719-728, Meier EHJ 2012;33:614-621))
Coronary blood flow is inversely related to coronary resistance. Coronary resistance is the sum of epicardial, precapillary arteriolar, and myocardial capillary resistances.2,5 Normal, non-diseased epicardial vessels are direct conduits and provide no resistance to blood flow. Precapillary arterioles connect the epicardial arteries to the myocardial capillaries and are the primary determinants of coronary resistance and flow. Smooth
muscle in the arterioles dilate and constrict to adjust to blood pressure over the range of 60-180 mmHg. The myocardial capillary bed forms an extensive network connecting each myocyte, often referred to as the microvasculature.
Coronary flow reserve (CFR) is the ability of the coronary circulation to augment coronary flow from a basal state to maximum hyperemia in response to physiologic or pathologic stimuli. It is expressed as the ratio of maximum hyperemic flow to resting flow and ranges from 2-5 in humans.2-4,6 Experimental animal studies have demonstrated that increasing epicardial stenoses beyond 60% diameter produces a gradual decline in maximal coronary flow, while stenoses beyond 80% impairs resting blood flow.7
3. Measurement of Coronary Blood Flow Human studies dating back 30 years have shown poor correlation with angiographic degree of stenosis and coronary blood flow. A study of 39 subjects undergoing coronary arterial bypass surgery demonstrated a very weak inverse correlation between angiographic stenosis severity and CFR (r = -0.25) despite good inter- and intra-observer agreement of angiographic severity.8 Even computer-based quantitative coronary angiography resulted in poor correlation of physiologic ischemia.9 The reason for this discrepancy is at least partially due to the multiple lesion characteristics that factor into physiologic significance, including minimal luminal dimensions and area, stenosis length, exit and entrance angles, reference vessel diameter, and diffuse coronary narrowing. Even after accounting for these parameters with intravascular ultrasound (IVUS), there still is disagreement between anatomic and physiologic assessment of lesion severity, which may be attributed to disease of the microvasculature.10 Physiologic assessment is therefore becoming the gold-standard for measurement of coronary stenosis severity in multiple clinical scenarios. Two methods of coronary physiologic assessment are relevant in clinical practice; angiographic flow estimation and direct intracoronary pressure and flow measurements. Other methods, like coronary sinus flow assessment,11,12 are beyond the scope of this review.
Angiographic Flow Estimation The Thrombolysis in Myocardial Infarction (TIMI) investigators developed several methods of estimating coronary blood flow using angiography. These qualitative and quantitative techniques have historically been studied in the setting of pharmacological and mechanical reperfusion therapies for acute myocardial infarction (AMI).
TIMI Flow Grade The simplest of methods to grade coronary flow rates is the TIMI flow grade, which is qualitatively assessed as contrast is injected into the artery of interest (Table 1).13 Normal TIMI 3 flow following pharmacological reperfusion therapy has been associated with improved outcomes, whereas lower TIMI flow grades have been associated with poorer outcomes.14
TIMI Frame Count A quantitative method of grading TIMI flow is the TIMI frame count (TFC), defined as the number of cine frames required for radiographic contrast to reach a standardized distal coronary landmark in the culprit vessel.15 The TFC can be further corrected by normalizing the TFC to the left anterior descending (LAD) coronary artery to obtain the corrected TFC (CTFC). (Since the LAD is longer than the other two epicardial arteries, the CTFC is calculated by dividing the TFC in the LAD by 1.7, a correction factor that normalizes the length of the LAD to the other two arteries.)15 The CTFC is a more precise measure of coronary flow than TIMI flow grades as evidenced by the fact that while normal CTFC is less than 20, CTFC of up to 40 is seen in TIMI 3 flow. Analysis of early thrombolytic trials demonstrated worse outcomes with CTFC >20 compared to normal CTFC, even if TIMI 3 flow is present (i.e. CTFC 20-40).16 Presence of high CTFC despite an open epicardial artery in the setting of AMI is thought to represent microvascular obstruction or dysfunction. The above methods are reproducible and have
minimal inter- and intra-observer variability, however injection rate and catheter lumen size may affect the frame counts by up to two frames.17
David P. Faxon, MD: Additional technical issues relate to the use of intracoronary bolus adenosine versus central venous or peripheral venous infusions. Studies have shown greater variability with intra-coronary bolus and peripheral venous administration. The current recommendations are for central venous infusion. (Jeremias et al Am Heart J 200;140:651-7) In addition administration of adenosine can result an initial greater coronary than peripheral vasodilatation resulting in falsely low FFR readings. It is recommended to wait until the pressure measurement stabilizes over a one minute before recording the FFR. (Tarkin et al Circ Cardiovasc Interv 2013;6:654-61)
TIMI Myocardial Perfusion Grade The TIMI myocardial perfusion grade (TMPG) is a semi quantitative assessment of myocardial perfusion originally developed by the Zwolle Myocardial Infarction Study Group in the Netherlands (Table 1).18 Unlike TIMI flow grade and CTFC, TMPG grades myocardial flow on the capillary level rather than on the epicardial vessel level. TMPG is assessed in the artery of interest by choosing the angiographic projection that best visualizes the supplied myocardium. Images are obtained with adequate injection allowing reflux of contrast into the aortic root. Injection is stopped after opacification of the coronary sinus, and cineangiography is continued until three cardiac cycles after myocardial blush begins to wash out. Low TMPG grade has been shown to be a poor predictor of outcomes after thrombolysis and percutaneous coronary intervention, despite the presence TIMI 3 flow, which indicates the importance of microvascular obstruction and dysfunction in this disease process.19,20
Wire-based Coronary Flow Measurements
Intracoronary guidewires engineered with pressure, Doppler, or temperature probes allow direct measurement of coronary pressure and flow. Such wire-based measurements are used to determine the significance of a coronary stenosis, assess the microvascular circulation, and gauge the physiologic response to mechanical or pharmacologic interventions.
The general technique is to place a 0.014” sensory angioplasty guide wire through a guide catheter into the coronary artery of interest after administration of intravenous heparin (40-60 Units per kilogram). Intracoronary nitroglycerin is often administered to maximally dilate the epicardial blood vessels. Once the wire is placed in the desired location, coronary hyperemia is pharmacologically induced by maximally dilating the resistance arterioles. This allows for the assessment of the epicardial vessel independent of the microvasculature. Intravenous adenosine is the most common agent used to induce hyperemia.21, 22
Direct Coronary Pressure Measurement – Fractional Flow Reserve Fractional Flow Reserve (FFR) is a lesion specific, physiologic index of the hemodynamic severity of intracoronary lesions and is the most commonly used invasive tool used to assess coronary flow. Its main strength is to identify lesions responsible for ischemia that in many cases would have been undetected or not correctly assessed by angiography alone.
FFR is defined as the ratio of the maximal flow to the myocardium in the presence of a coronary stenosis normalized to the theoretical maximal flow in the same artery without a stenosis. Normal FFR is 1.0 and suggests that flow in the distal vessel is normal; an FFR of 0.50 suggest half normal maximal flow in the distal vessel. FFR uses the principle of pressure loss: pressure distal to a significant stenosis is lost to friction, turbulence, and flow separation.23 The pressure gradient across a stenosis is related to flow in a curvilinear manner, allowing pressure to be used as a surrogate for flow in the calculation
of FFR.24 Experimentally-derived equations to determine FFR of the myocardium (FFRmyo), coronary artery (FFRcor), and collateral circulation (FFRcollateral) are as follows, where Pd, Pa, Pv, and Pw are the mean distal, aortic, venous, and wedge pressures:25,26 FFRmyo = (Pd –Pv) / (Pa – Pv) FFRcor = (Pd – Pw) / (Pa – Pw) FFRmyo= FFRcor + FFRcollateral In clinical practice, FFRmyo is used to determine FFR of the coronary territory of interest, and is simply the ratio of distal coronary to aortic pressure (Pd/Pa), assuming negligible contribution of Pv to the equation. Commercially available guidewires that contain a pressure sensor at the end of the radio-opaque portion of the wire allow for easy measurement of FFR.
David P. Faxon, MD: Coronary collateral flow is difficult to assess but can be estimated with PET imaging, contrast echo, angiography and by pressure or flow measurements. The most common method is to use pressure measurement and the following formula.
CFI = (Pocc – CVP)/Pa – CVP)
Where CFI is coronary flow index, Pocc is the pressure downstream from the occlusion, CVP is the central venous pressure and Pa is the mean aortic pressure. FFR takes into account collateral flow but by its self is not able to separate the component due to flow through the stenosis and flow from collateral flow. (Seiler Circ Cardiovasc Interv 2013;6:719-728)
Initial studies of FFR in humans demonstrated that FFR of 0.75 or less had very good sensitivity and specificity for detecting myocardial ischemia.27-29 Subsequent studies demonstrated a cutoff FFR of less than 0.80 to have better sensitivity, suggesting that FFR 95% reproducibility for determining whether lesions were ischemic when outside the FFR range of 0.75-0.85 (Figure 1). However, in the 0.77-0.83 FFR range reproducibility is diminished (there was only 50% reproducibility at FFR 0.80), implying that the biologic variability between measurements creates a “measurement gray zone”.31 David P. Faxon, MD: Other recognized limitations of FFR is the measurement of serial stenosis and stenosis involving bifurcations that are discussed later, Since FFR is dependent on the size of the myocardial perfusion bed, proximal stenosis are more likely to have a positive FFR than distal stenosis. Likewise in the presence of infarcted myocardium, the viable myocardial bed is smaller and FFR is higher. The FFR in this setting accurately reflects the degree of myocardial ischemia however. (Pijls J Am Coll Card 2012;59:1045-57) One additional situation that can lead to false FFR is in multi-vessel disease that involves major branches. For instance when there is an intermediate stenosis in the left main and a high-grade stenosis in the LAD, the FFR in the circumflex (reflecting the LM stenosis) will be falsely high (less significant) due to a significant reduction in the size of the myocardium served by the LM. (Yong et al Circ Cardiovasc Interv 2013;6:161-5)
One of the advantages of FFR stems from the real-time nature of Pd and Pa measurement making FFR independent of systemic blood pressure and heart rate.23 In addition, the measurement reflects the contribution of epicardial stenosis independent of the microvasculature of the supplied myocardium and can be reliably interpreted in multivessel disease, infracted myocardium, and areas with collaterals. Examples of FFR measurements are demonstrated in Figure 2.
FFR Limitations FFR operates under two assumptions that limit its applicability in some clinical situations. It assumes a linear relationship between pressure and flow, when in fact it is curvilinear.24,32 The use of the true FFRmyo equation may in part compensate for this, but it is too cumbersome to use in daily clinical practice. . In addition, FFR assumes minimal resistance from the microvasculature after peak vasodilation, an assumption that may break down in cases of left ventricular hypertrophy, conditions associated with extensive microvascular damage, or in high baseline flow states such as sepsis or liver disease.33 As with all clinical measurements, FFR may be limited if special care is not taken to ensure careful and accurate sampling. For example, inaccuracies in transducer “zeroing” and normalization of the proximal aortic pressure may dramatically alter the measured FFR ratio..34 Direct Coronary Flow Measurement – Coronary Flow Reserve Coronary flow reserve (CFR), also known as coronary vasodilatory reserve (CVR) or coronary flow velocity reserve, is no longer routinely used in clinical practice because of several limitations (see below) and the ascendance of more user-friendly FFR methods. CFR is defined as the ratio of maximal to basal coronary flow, and can be measured in an individual artery using Doppler or thermodilution methods. Normal CFR in humans exceeds 3.0, while a CFR of 0.80, as well as improvement in clinical outcomes when PCI is performed on top of optimal medical therapy in patients with FFR ≤ 0.80.
Multivessel Disease It has been long recognized that myocardial SPECT is limited in identification of multiple vascular territories affected by multivessel disease.52 In the era of bare-metal stents, a retrospective analysis 102 subjects with multivessel disease in which one artery was treated by PCI and at least one stenosis was deferred from PCI based on an FFR > 0.75 revealed low overall major adverse cardiac events (MACE, 9% and 13% at 12 and 36 months, respectively), with 6.3% related to one of the deferred vessels and 12.2% related to the initially treated artery.53 In addition, prospective, nonrandomized study of 137 consecutive subjects with multivessel disease who underwent FFR-guided PCI (n = 57) or conventional PCI (n = 80), with a cutoff FFR of
