CHAPTER 34: CORONARY BLOOD FLOW AND MYOCARDIAL ISCHEMIA

Low coronary blood flow causes acute coronary syndromes (ACS), angina pectoris, myocardial infarction, impaired left ventricular (LV) function, heart failure, arrhythmia, and death. High coronary blood flow capacity associates with cardiovascular health; its variations, reflecting our emotional states, lifestyles, and food, even the postprandial lipid surge of the last meal, are all documented to alter coronary blood flow and risk factors, symptoms, and outcomes of coronary artery disease. Evolving from 200 million years ago, concepts regarding the mammalian heart—coronary blood flow, human gender evolution, fluid dynamic equations, coronary pressure flow measurements, quantitative perfusion imaging, diagnostic tests, coronary artery disease in women versus men, and how poor coronary flow is optimally treated—constitute a highly integrated continuum, a syncytium of knowledge immediately relevant to current cardiovascular medicine and patient well-being.

Resurgent interest in coronary blood flow related to myocardial “ischemia” derives, in part, from substantial disconnects in cardiovascular medicine. Immediate percutaneous coronary intervention (PCI) in ACS reduces myocardial infarction and cardiovascular mortality.¹ However, all elective revascularization trials driven by “ischemia” on diagnostic testing fail to reduce myocardial infarction or cardiovascular deaths despite relief of angina^{2,3,4,5,6,7,8,9} (Fig. 34–1).

This disconnect even reaches into the legality of fully informed consent wherein “cardiologists (95%) in this sample did not inform the patient that PCI would not lower the risk of death or MI [myocardial infarction], or that the symptom benefit is gone after 5 years.”^10,11 This issue is particularly relevant in view of only half of procedures being classified as appropriate out of 145,000 elective PCIs of the National Cardiovascular Data Registry.¹²

Moreover, the rationale for all diagnostic tests, prognosis, treatment, and procedures for coronary artery disease (CAD) invokes coronary blood flow that is not measured, used clinically, and poorly understood. Finding “ischemia” for the diagnosis of CAD should no longer be the sole, the primary, or even an adequate goal of diagnostic testing, because most CAD is best treated medically for optimal outcomes. The essential evidence-driven goal of “diagnostic” testing now requires objective identification of those patients with quantitative physiologically severe CAD of sufficiently high risk that revascularization reduces risk of myocardial infarction or mortality in addition to providing relief of angina.

These disconnects in cardiovascular medicine require us to rethink the term ischemia because its specific definition, or rather many potential definitions, highlights the core issues of CAD: how is it quantified, and for what goal—diagnosis, progression/regression, medical treatment, or revascularization? This chapter addresses these disconnects by integrating coronary blood flow, myocardial ischemia, coronary pathophysiology, angiographic anatomy, diagnostic testing, and treatment trials into a rational synthesis for clinical practice.

Myocardial ischemia, reversible ischemia, or its absence, is considered or invoked in virtually every aspect of every patient evaluated for CAD. Diagnostic test reports, clinical history, verbal discussion, risk stratification, long-term prognosis, clinical decisions, management, and outcomes all utilize or report evidence of ischemia (or not). It is associated with adverse outcomes as the basis for treatment or interventions intended to prevent ischemia and associated coronary events. Myocardial ischemia is an emotionally loaded, general term conjuring up a sense of life-threatening badness or “cardiovascular evil” that demands immediate action.

These associations are explicitly formalized in the concept of the ischemic cascade embedded in clinical practice as relentless progression demanding intervention. In restricted circumstances, such as ACS, this view has some statistical or trial justification with proven modest reduction of myocardial infarction or death by immediate PCI.¹ However, in many other circumstances, the diagnosis of ischemia carries no such adverse risk, thereby misguiding management with no benefit^{2,3,4,5,6,7,8,9,10,11,12} and possibly more potential patient harm than benefit from revascularization in some circumstances.

The wide range of meaning for myocardial ischemia is obvious when trying to define or quantify it as one or more of the specific conditions listed in Fig. 34–2. Each of these definitions is a physiologic end point or measurement having greater or lesser importance and effectiveness for optimal patient outcomes depending on their severity, rate of development, their different combinations together, and clinical circumstances. Therefore, actionable use of the term myocardial ischemia requires definition of a specific measurement, its severity, and its time course. Additionally, trial evidence of treatment or interventions that alter symptoms, cardiac function, and coronary events or survival, using those quantitative measures of ischemia, is needed to guide treatment.

Traditional textbooks or training approaches to myocardial ischemia start with the process, procedures, and paradigm of clinical cardiology. This traditional training paradigm of clinical cardiology typically begins with the prevalence and demographics of CAD, pathology of atherosclerosis, plaque rupture, elements of the ischemic cascade, noninvasive diagnostic tests, their sensitivity and specificity, and risk stratification. This is followed by details of medical treatment and invasive interventions for assumed benefit. Alternatively, particularly in medical school, the training paradigm starts with pure basic physiology as separate, primary, commonly experimental knowledge independent of and somewhat unrelated to cardiology practice.

The traditional myocardial ischemia paradigm imbues generations of cardiologist in the processes and procedures of cardiovascular medicine as the standard of community care with expected benefit by patients and physicians reinforced to some extent by fee-for-service–oriented tests and procedures. However, the failure of randomized revascularization trials to reduce myocardial infarction or coronary deaths compared to medical treatment alone in “stable CAD” challenges this training and practice paradigm.^{2,3,4,5,6,7,8} Whether defined clinically, symptomatically, or by any diagnostic test for CAD, this well-documented failure to reduce myocardial infarction or mortality requires rethinking the meaning and use of the term myocardial ischemia—its definition, quantification, time course, pathophysiologic meaning, management, its noninvasive and invasive testing, outcomes, and therefore cardiology textbooks and training.

The science of randomized trials drives a sharp edge into tradition versus change, into group statistics versus individual personalized medicine, and into the economics or business versus evidence-based practice of cardiovascular medicine. This chapter on myocardial ischemia addresses this edge by changing the traditional training-practice paradigm to reorient the reader’s mindset. We start with the outcomes of randomized revascularization trials—success and failures, that biting edge, the purpose of cardiovascular medicine. Trial outcomes provide a powerful lesson on coronary pathophysiology with insights into the mechanisms and quantitative measures of ischemia thence leading directly into the critical role of quantitative coronary blood flow (myocardial perfusion) to assess physiologic severity of CAD for binary clinical decisions, diagnostic testing, interventions and management of ACS or chronic stable CAD

Clinical training, practice, and research require a new mindset based on benefit to patients proven in randomized trials, rather than the traditional clinical or pure physiology paradigms that assume patient benefit without objective scientific basis. These trials provide clear evidence for an integrated conceptual chain from outcomes to treatment, to measures of severity, its time course, its relevant pathophysiology, its quantitative methodology, and routine diagnostic testing. Clinical coronary pathophysiology is essential for integrating this outcomes-driven chain of reasoning toward evidence-based personalized management. Within the continuum of coronary pathophysiology, randomized revascularization trials divide our approach to myocardial ischemia into two parts—ACS and nonacute or stable CAD.

Accordingly, we start with ACS as manifestations of ischemia caused by low coronary blood flow for which revascularization reduces coronary events and mortality¹ without preangiogram noninvasive testing or invasive quantitative measurements. Beginning with the outcomes of intervention trials in acute syndromes, we reveal profound pathophysiologic insights into noninvasive cardiac testing and management of “stable CAD”—indeed, the entire current paradigm of cardiovascular practice and economics or “business” of medicine. Diagnosis of CAD has been and will substantially remain the goal for all noninvasive testing and diagnostic angiograms. However, randomized trials and advanced imaging technology are driving “diagnostic” testing for ischemia toward a more advanced purpose beyond just diagnosis to the primary guide for invasive procedures and revascularization. This reasoning requires us to rethink ischemia because its specific definition, or rather many potential definitions, highlights the core issues of CAD: how should it be quantified and for what goal—diagnosis, progression/regression, medical treatment, or revascularization?

ACS now account for 70% to 80% of PCIs, with the remainder for nonacute or stable CAD.^13,14 ACS are categorized as unstable angina or myocardial infarction with ST-segment elevation (STEMI) or without ST-segment elevation (NSTEMI). In randomized trials, acute revascularization improves LV function, and reduces death, subsequent myocardial infarction, and long-term mortality.¹ Immediate primary PCI gives the best outcomes without preangiogram diagnostic tests, imaging, or intravascular diagnostic measurements.

The definitions or measures of ischemia in these syndromes provide lessons in clinical pathophysiology relevant to stable CAD and diagnostic testing. STEMI is defined by elevated cardiac specific enzymes with ST-segment elevation on electrocardiogram (ECG) and acute onset of symptoms. Coronary angiogram typically shows a severe coronary stenosis or thrombus and regional LV dysfunction. Unstable angina typically has acute onset of definite chest pain and or typical associated symptoms, commonly with nonspecific ECG changes without diagnostic enzyme rise.

However, even in these acute syndromes for which acute PCI reduces myocardial infarction and mortality, the actionable definition of ischemia is not unique or singular. Acute characteristic symptoms in one case, cardiac enzymes in another, acute ECG changes in another, all indicating ischemia or injury, as commonly used interchangeably, with benefit by revascularization. These different manifestations or criteria of ischemia reflect a more basic commonality—reduced coronary blood flow reflecting anatomically and physiologically severe coronary artery stenosis, thrombosis, and spasm.

Other than ECG and cardiac enzymes for characteristic ACS, the coronary angiogram with potential PCI is indicated without requiring preangiogram diagnostic testing or measures of severity because clinical ACS documents severity sufficient to benefit by PCI reducing myocardial infarction or death. For less clear clinical manifestations or for nonacute CAD, diagnostic testing for quantitative anatomic or physiologic severity becomes the essential guide for revascularization. Therefore, stenosis severity in ACS establishes a severity threshold for which revascularization definitively reduces myocardial infarction rate and mortality. Quantifying that threshold and the pathophysiology leading to ACS provides insight into quantitative severity by “diagnostic tests” in stable CAD for which intervention might provide similar benefit that is not yet demonstrated in intervention trials in stable CAD.

The schematic of Fig. 34–3 illustrates the pathophysiologic sequence of recurrent subclinical plaque ruptures leading to an ACS.^15,16,17 Eighty-nine percent of acute fatal coronary events result from a series of preceding, subclinical, small plaque ruptures that heal with progressive narrowing to a severe stenosis; the final plaque rupture that was previously subclinical finally occludes the small remaining lumen, with myocardial infarction. Most of these subclinical small plaque ruptures heal and stabilize without occluding the relatively large lumen before the final plaque rupture occludes the evolving narrowed artery. A large nonstenotic lumen with an initial single occlusive plaque rupture explains only 11% of fatal infarctions at pathologic examination.¹⁵

Intracoronary optical coherence tomography–intravascular ultrasound (OCT-IVUS) in ACS demonstrates severe focal lumen narrowing averaging 72% ± 13% diameter stenosis (DS) superimposed on varying severity of diffuse disease.¹⁶ The OCT-IVUS finding confirms in patients the high-risk severe stenosis superimposed on diffuse disease in ACS. This progression to severe stenosis by serial plaque ruptures may develop over days, weeks, months, or years, thereby explaining the continuum of clinical manifestations from ACS to chronic “stable” CAD of varying severity.^{18,19,20,21,22}

The anatomic and physiologic severity of CAD associated with ACS defines that severity threshold at which revascularization may reduce myocardial infarction rate and mortality in nonacute CAD. Extrapolating these thresholds to cardiac testing and management of chronic “stable” CAD requires conceptual integration with coronary pathophysiology, coronary blood flow (or myocardial perfusion), stenosis pressure gradients, the quantitative coronary angiogram, and specific definitions of ischemia as the basis for managing CAD.

In contrast to anatomic stenosis severity by OCT-IVUS in ACS, coronary blood flow in ACS has not been defined because the clinical circumstances demand immediate intervention. However, coronary blood flow for comparable anatomic severity has been documented in several different ways: (1) comparable stenosis of in vivo experimental models where coronary blood flow is measured, (2) quantitative myocardial perfusion during stress positron emission tomography (PET) imaging in patients having angina and significant ECG changes comparable to ACS, (3) quantitative perfusion in a large study of patients with and without CAD with and without revascularization for comparative ranges of perfusion, and (4) precise fluid dynamic modeling of stenosis and diffuse narrowing in simulations of pressure flow behavior of the entire coronary artery tree.

Experimental Coronary Stenosis

Experimental models link severity of coronary blood flow with precise anatomic stenosis comparable to that measured by OCT-IVUS at ACS. Because of high coronary bed resistance at resting conditions, coronary artery stenosis does not cause enough resistance to affect resting flow until 85% to 90% DS, as seen in Figs. 34–4 and 34–5.²³ However, the reserve capacity to increase flow begins to fall at 65% to 70% DS. This reserve capacity, or coronary flow reserve (CFR), is the ratio of absolute stress flow to rest flow in absolute units of cc/min for arterial flow or cc/min/g for myocardial perfusion, also called myocardial perfusion reserve (MPR). Because of the extensive literature on fluid dynamic, experimental, and clinical data, we use the terms CFR and MPR interchangeably here, with specific units of flow in cc/min or perfusion in cc/min/g as appropriate.

The term maximal hyperemia of coronary flow for quantifying CFR derives from the initial experimental vasodilatory stimulus—reactive hyperemia that is the marked rapid rise in coronary blood flow to maximum after transient coronary occlusion for 10 to 20 seconds. As addressed in a later section on control of coronary blood flow, this basic physiologic phenomenon of maximal hyperemia occurs after every systolic contraction and after every balloon deflation at PCI, with little awareness of its physiologic significance.

Experimentally and clinically, maximal hyperemic flow for determining CFR is achieved pharmacologically by arteriolar vasodilating drugs such as contrast media in early experiments, followed by dipyridamole, adenosine, ATP, and regadenoson. Dobutamine is an alternative sympathomimetic stressor producing near-maximal hyperemia for determining CFR. Although exercise increases coronary blood flow, it cannot be measured during upright treadmill exercise that precludes obtaining the arterial input function required for quantitative myocardial perfusion imaging. Although similar for most diagnostic purposes, vasodilator, exercise, and sympathomimetic stressors have some differences that are clinically relevant, as reviewed in the chapter on PET imaging (Chap. 19).

Progressive coronary narrowing reduces CFR with little change in resting flow until an approximately 80% to 90% DS on high-resolution cut film angiograms with a measured resolution of 10 to 11 line pairs per millimeter and/or by a mechanical stenosis caliper. At this severe stenosis, resting flow falls but some residual CFR capacity remains on pharmacologic vasodilator stimulus, as seen in Fig. 34–5 in the vertical red zone.²³ Stenosis severe enough to reduce resting perfusion does not elicit all remaining reserve vasodilator capacity because of a remarkable self-regulating mechanism that protects subendocardial perfusion by mechanisms further explained in the later section on myocardial steal.

At such severe stenosis reducing resting perfusion, any increase in vasodilator-mediated increased coronary flow causes a proportionately greater severe fall in coronary perfusion pressure, thereby reducing subendocardial perfusion more than subepicardial perfusion, causing subendocardial ischemia, angina, and ST-segment depression on ECG. The coronary control mechanisms that prevent invoking maximal vasodilatory capacity thereby prevent the fall in perfusion pressure and associated subendocardial ischemia. When exercise or pharmacologic vasodilation forces greater vasodilation than stable resting conditions, this protective control is overridden with ensuing subendocardial ischemia.

The red zones of Fig. 34–5 highlight the anatomic severity, 80% to 90% DS, and the physiologic severity at which rest flow falls below normal resting demands to potentially “ischemic” flow levels. While in the same severe range, the experimental stenosis of 80% to 90% DS appears somewhat worse than the average 72% ±13% DS superimposed on a large burden of diffuse disease observed by OCT-IVUS, causing low enough coronary flow for ACS.¹⁶ The experimental models of isolated stenosis do not have the underlying diffuse disease observed by OCT-IVUS in ACS. Therefore, a 72% DS superimposed on diffuse disease would expect to have an effect on coronary flow comparable to a more severe isolated stenosis of 80% to 90% diameter narrowing without underlying diffuse disease.^24,25,26

At such severe stenosis, the anatomic severity parallels severe flow reduction in both experimental, clinical correlations, and fluid dynamic models. Regardless of the mechanical cause of stenosis—structural narrowing, plaque rupture or hemorrhage, thrombosis, or spasm—ACS result from low coronary flow caused by severe stenosis commonly superimposed on diffuse disease in varying proportions. Consequently, the experimental anatomic severity would be expected to be somewhat worse than clinical stenosis superimposed on diffuse disease for a given limitation on CFR or stress flow. For less severe stenosis superimposed on predominantly diffuse disease, the discordance between anatomic severity or percent DS and coronary flow capacity becomes more common as reviewed further below.

Clinical Quantitative Perfusion Imaging of CAD Severity

In a large series of patients with angina, significant ECG changes and severe regional perfusion defects during dipyridamole infusion, the quantitative stress perfusion was 0.91 cc/min/g and CFR 1.7, shown in Fig. 34–6.²⁷ This low flow threshold causing ischemia in patients compares to the threshold of CFR and percent DS at which resting flow falls in the experimental model of Fig. 34–5, and compares to the 72% DS superimposed on diffuse disease seen in ACS.¹⁶

In a large clinical study (N = 1674), the low flow threshold of 0.9 cc/min/g and CFR of 1.7 associates with angina, ECG changes, and a severe regional stress defect (Fig. 34–7).^25,26,27,28 In these same patients, the relative severity of stress perfusion defects at this ischemic low flow was 0.59. These thresholds at which angina and ST-segment changes develop are substantially lower than in patients without angina or ST-segment changes during dipyridamole stress, either with or without revascularization, shown by the red zones of Fig. 34–7.^25,26,27,28 ECG-gated PET perfusion images typically show associated impaired regional LV contraction or fall in ejection fraction compared to resting baseline. Importantly, global CFR and stress perfusion in cc/min/g were reduced in parallel with, but less severe than, the regional stress defects, thereby indicating a substantial burden of diffuse CAD underlying the worst flow-limiting stenosis.

Regardless of the mix of regional stenosis or diffuse disease causing these low-stress flows, the thresholds of perfusion in cc/min/g and CFR correlate closely with angina and significant ST-segment changes. Most patients with angina and ECG changes had predominantly severe regional stress perfusion abnormalities superimposed on diffusely reduced stress perfusion reflecting diffuse disease, consistent with OCT-IVUS findings and pathology studies. A significant minority of these patients had severe regional stress perfusion abnormalities with good global flow capacity throughout the remainder of the heart, indicating little diffuse narrowing. Another significant minority had less severe relative regional stress defects superimposed on severely reduced global stress perfusion, indicating relatively more severe diffuse flow-limiting disease, as reviewed in the chapter on PET imaging (Chap. 19).

Fluid Dynamic Models of Stenosis and Diffuse Narrowing

Correlating or predicting physiologic severity from angiographic anatomy, or vice versa, is limited by the modest but real limited resolution and variability of clinical angiographic anatomy and myocardial perfusion measurements. In addition, standard angiography does not account for effects of diffuse CAD. Experimental stenosis with high-resolution angiograms, accurate flow meter measurements, and absence of diffuse disease provide accurate enough data to confirm the applicability of theoretical fluid dynamic equations for stenosis in the absence of diffuse disease.^{23,29,30,31,32} However, clinical OCT-IVUS observations,^{16,17,18,19,20,21,22} pathology findings,¹⁵ and quantitative perfusion in patients^{24,25,26,27,28,29} illustrated in Figs. 34–3 and 34–7 indicate the critical role of diffuse CAD underlying most focal stenosis.

In the absence of a clinical or experimental anatomic measure of diffuse disease cumulatively throughout the entire coronary artery tree, fluid dynamic simulations of stenosis and diffuse narrowing in Fig. 34–8^24,26 provide important insights consistent with clinical observations. These precise computer models of stenosis and diffuse narrowing are based on the dimensions and vascular bed sizes reported for the human branching coronary artery tree.^33,34,35,36 The model accounts for interacting viscous pressure loss of diffuse narrowing and vortex shedding or turbulent flow caused by segmental stenosis in varying proportions. The calculated CFR and stress flows match the experimental model for stenosis. They also correlate reasonably with clinical anatomic and physiologic quantification of stenosis with minimal diffuse narrowing evidenced by good global CFR and stress flow in patients.

Coronary flow is a function of the arterial radius raised to the fourth power. Consequently, in Fig. 34–8, the small DS change from 69% to 74% DS reduces CFR from 2.0, associated with low risk, to 1.5, associated with high risk, in large clinical studies reviewed in detail. Diffuse 30% diameter narrowing reduces CFR to 2.0, associated with low risk. With minimal further diffuse narrowing to only 37% diameter, diffuse narrowing reduces CFR to 1.5 and high risk of coronary events. A modest stenosis superimposed on mild diffuse narrowing reduces CFR to low levels associated with high risk, where as either alone causes no significant high-risk reduction in CFR.

Even for these precise computer models of stenosis, the difference in DS is not visually obvious and diffuse narrowing cannot be seen in the absence of a “normal” reference. As subsequently addressed, the resolution of clinical angiograms is not adequate to quantify such small anatomic differences between high-risk and low-risk physiologic severities of stenosis. Consequently, anatomy-derived predictions of physiologic severity incur such poor accuracy and imprecision as to preclude them from reliably guiding clinical decisions on revascularization procedures based on physiologic severity of CAD.

These separate streams of data associated with stenosis severity in ACS suggest a critical threshold of CFR and stress perfusion resulting from physiologically severe high-risk CAD that may benefit from revascularization. This threshold may also serve to prevent unnecessary procedures incurring greater risk than medically treated disease, thereby leading to nonacute CAD, diagnostic tests, and physiologically guided treatment trials.

In contrast to ACS,¹ revascularization trials in nonacute CAD have not reduced myocardial infarction rate or mortality,^{2,3,4,5,6,7,8,9,10,11,12} as illustrated in Fig. 34–1. However, randomized trials of intervention guided by fractional flow reserve (FFR) provide important insights on physiologic severity.^{37,38,39,40,41} Although not definitive for reducing myocardial infarction or mortality by classical intention-to-treat analysis, the Multicenter Randomized Study to Compare Deferral Versus Performance of PCI (DEFER)³⁷ and Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) trials^38,39,40,41 provide additional strong support confirming physiologic stenosis severity as the potential optimal guide to whether revascularization or medical treatment should be used.

FFR was first introduced 23 years ago as a potential clinical tool. It has spurred a major evolution in cardiology from angiogram anatomy to coronary physiology as the scientific basis for assessing stenosis severity to guide revascularization.⁴² As used clinically, FFR is calculated as the ratio of pressure distal to a stenosis to aortic pressure during maximal pharmacologic hyperemia, typically intracoronary or intravenous adenosine,⁴² as illustrated in experimental pressure-flow recordings of Fig. 34–9.^25,43 FFR is comparable to relative CFR but not absolute CFR derived from perfusion in cc/min/g, the consequences of which incur discordances addressed later. The FAME 1 trial^38,39 showed that FFR-guided PCI reduced major adverse coronary events (MACE) compared to angiogram-guided intervention (Fig. 34–10).³⁸

Based on traditional intention-to-treat analysis, the FAME 2 trial using FFR criteria of 0.8 for PCI showed no reduction in rate of myocardial infarction or death compared to medical treatment in nonacute CAD^40,41 (Fig. 34–11). However, Landmark Analysis beginning 1 week after the PCI excluded procedure-related events in the first 7 days to show significantly reduced MACE in the PCI versus medical treated group after the first postprocedure week. Therefore, for an FFR threshold of 0.8, the reduced MACE after the first week following PCI was balanced out by an increased risk of MACE (factor of nine) associated with the procedure within the following week. Consequently, PCI had no net benefit on reducing risk of MACE. Because greater stenosis severity associates with higher risk of MACE,⁴⁴ the data suggest that at a lower, more severe threshold than 0.8, PCI might potentially reduce MACE more than the reported risk of the procedure, thereby providing net benefit at long-term follow-up by intention-to-treat analysis.

The original reports on FFR in patients (DEFER)³⁷ used a threshold of 0.65. Despite a lack of trial evidence, the threshold has increased to 0.8 over the ensuing years, likely related to its application in multivessel disease that includes diffuse disease. Figure 34–12 documents the continuum of severity and risk from meta-analysis of FFR measurements compared to MACE outcomes.⁴⁴ Severity-driven risk is an established general concept, but quantification of physiologic severity by FFR versus risk provides important new insights. The intercept of the severity-risk–benefit curves at the black dot of Fig. 34–12 defines the threshold at which the benefit of PCI balances the risk of the disease: here 0.67 from all reports on PCI outcomes at the time of analysis.

In Fig. 34–12, choosing an FFR threshold at the intercept, or at severities close to it on either side of the intercept, would have little net benefit or harm because of the overlap of the probability ranges for severity risk curves. At thresholds further toward lower FFR and greater physiologic severity, the benefit of revascularization can be more readily detected if it exists. Note that the relative severity of PET perfusion images at 0.59 associated with stress angina and ECG changes in Fig. 34–7 compare to the severity of FFR in Fig. 34–12 expected to have net reduction in MACE over medical treatment.

The evidence-driven scientific basis for management of CAD has evolved from anatomic angiographic to physiologic severity of CAD, incurred by widening use of pressure-based, FFR-guided elective interventions. However, FFR has some limitations, was derived from the original concepts of CFR, and has been validated by quantitative PET absolute perfusion in cc/min/g. As for most science, each major advance establishes a springboard for the next step—here FFR leading to quantitative myocardial perfusion to guide CAD management. Evolving physiologic severity to guide management beyond FFR will likely parallel remaining dominance of the coronary angiogram in CAD management. However, transcatheter therapeutics have and will increasingly rely on physiologic severity rather than the past dominant role of the angiogram. The current major gap in cardiovascular medicine/interventions is absence of randomized revascularization trials with myocardial infarction or mortality end points guided by integrated, comprehensive, quantitative physiologic severity of stenosis and diffuse CAD based on combined stress perfusion and CFR.

Because anatomic severity by OCT-IVUS defines critical physiologic stenosis severity underlying ACS, why has the coronary angiogram severity failed to identify patients for whom revascularization also reduces risk of myocardial infarction or death in nonacute CAD? Early and recent literature shows a severity risk relation as seen in Fig. 34–13. Panel A from old literature shows average angiographic percent DS related to subsequent occlusion at follow-up angiogram,^45,46 regardless of clinical events and obviously not accounting for deaths. Panel B shows recent data with similar power curves relating the angiographic SYNergy Between PCI With TAXUS and Cardiac Surgery (SYNTAX) score to mortality at different follow-up intervals.⁴⁷ These correlations of average percent DS with outcomes confirm a severity-risk continuum as for FFR in Fig. 34–12.

However, angiographic severity to guide revascularization has not identified patients for whom these procedures reduce rates of myocardial infarction or death. There are three possible reasons: (1) revascularization procedures do not benefit patients with any severity of nonacute CAD; (2) the percent DS threshold guiding procedures is not severe enough with insufficient risk to benefit from the procedures; and (3) resolution of the clinical angiogram is inadequate to define the critical difference between high-risk, low-flow capacity stenosis and mild-to-moderate low-risk, adequate-flow stenosis.

In view of beneficial intervention in ACS, the latter two alternatives likely answer the question above, as illustrated in Fig. 34–14.²⁸ The PET scan shows a severe large-stress defect leading to the angiogram and stenting with follow-up angiogram. Quantitative analysis of the angiogram reported an average 83% DS tapering stenosis seen visually. The computer simulations in panels A, D, and E are precise simulated stenosis of 67% DS, 75% DS, and 83% DS with their fluid dynamically calculated CFR associated with low or high risk. Panels B and C are the angiogram of a plastic stenosis model of 67% DS filled with contrast media without heart motion or other factors degrading angiogram quality.

The limited resolution of the angiogram³⁴ with loss of border resolution makes it look worse than its true 67% DS associated with adequate CFR associated with low risk. In this critical range, even precise simulated stenosis from 67% to 83% DS is not readily distinguished visually, and certainly not quantifiable by automated quantitative angiographic analysis. At the critical threshold of 75% to 83% DS associated with low CFR and high risk, the angiogram cannot identify those patients with physiologically severe stenosis who may benefit from revascularization more than the risk of the procedure.

Finally, in past and current trials, it is likely that patients with objectively measured stenosis of 67% to 83% DS would not be randomized to medical treatment or revascularization because of preexisting bias that those randomized to medical management would suffer unethical withholding beneficial treatment. The same bias now applies to the FFR threshold of 0.8 despite the fact that angiographic severity or FFR as now used does not identify patients for whom revascularization reduces rate of myocardial infarction or death despite reducing angina, as discussed above.

An extensive literature documents the relation of CFR and cardiovascular risk, as recently reviewed^25,26 and confirmed in a large patient cohort (Fig. 34–15).^48,49 Global CFR by PET, reflecting the global burden of diffuse and segmental CAD in a large cohort of patients, showed high risk for global CFR less than 1.5 compared to low risk for global CFR greater than 2.0 and intermediate risk for CFR between these values. In this nonrandomized study, PCI or coronary artery bypass (CAB) in patients with global CFR over 2.0 had no benefit over medical treatment on mortality. For global CFR less than 1.5, PCI had no benefit over medical treatment, as expected for severe diffuse CAD. However, patients with global CFR less than 1.5 undergoing CAB had significantly better survival than medical treatment. Although the data are not definitive in the absence of a randomized trial, they are consistent with the quantitative severity-risk relations discussed above, all leading to a unifying synthesis on physiologic severity of stenosis and diffuse disease for guiding management of CAD.

This overview derived from ACS benefited by revascularization establishes the relevance of coronary blood flow and clinical coronary pathophysiology, stenosis pressure gradients, and quantitative diffuse disease in management of CAD. Figure 34–16 (central illustration) summarizes the concept for the various measures of severity outlined above.⁵⁰ The continuum of quantitative severity versus risk likely explains, in part, the failure of all trials using all of these technologies to identify those patients having physiologically severe enough CAD to benefit optimally with revascularization or medical treatment alone. In the severity-risk continuum, less severity associates with procedural risk higher than risk of the disease and, therefore, patient harm. Progressively greater severity associates with higher risk most likely to benefit from revascularization over the risk of the procedure plus risk of medical management. Of course, there is no randomized trial to prove this view, and there may not be one, given the general unwillingness to randomize patients with more severe disease on the left of the curves intersection (the red dot).

Although FFR has had a profound beneficial influence on moving the scientific basis for assessing coronary stenosis from angiogram anatomy to physiologic severity, it has several clinically important limitations. It requires invasive coronary pressure measurements at coronary angiogram that commonly bypasses physiologic measurements. By increasing costs of the cardiac catheterization and potentially reducing revenues by eliminating stent procedures, it is not widely considered as economically favorable for slim catheterization laboratory margins. Scientifically, FFR discordance with CFR by flow velocity wires or by quantitative PET perfusion imaging shown in Fig. 34–17³³ is an unresolved issue for which measurement should guide PCI. The discordances are comparable in both invasive pressure-flow velocity correlations as well as correlations between relative CFR, analogous to FFR, versus absolute CFR by quantitative PET imaging.^25,33 These discordances arise primarily from FFR, reflecting relative as opposed to absolute CFR derived from quantitative perfusion in cc/min/g.

For example, consider the orange region of Fig. 34–17,³³ where vasodilatory capacity is preserved with CFR of 3.0 associated with a large pressure gradient and FFR less than 0.8. Such high flow capacity is associated with low risk on medical treatment, as seen in Fig. 34–15, and is well above ischemic flow levels at CFR of 1.7 in patients having angina and ST-segment changes of Figs. 34–6 and 34–7. In this report relating CFR to FFR,³³ 19% of cases had high-flow, low FFR discordance typical of mild-to-moderate focal stenosis with high flow capacity preserved by minimal diffuse or small-vessel disease, the orange region of Fig. 34–17. At the opposite end of the continuum, 21% of patients fell into in the yellow region of Fig. 34–17, with severely reduced CFR and an FFR greater than 0.8. This discordance is caused by severe diffuse disease reducing CFR without significant focal stenosis, causing a stenosis gradient with high FFR. As in Fig. 34–15, such low global CFR or stress perfusion associates with high-risk disease for which bypass surgery may reduce risk of myocardial infarction and death despite high FFR, but this concept requires testing in randomized trials.

FFR has similar discordance with angiographic severity separately from the issue of precise angiographic quantification of stenosis. Inclusion criteria for FAME 1^38,39 and FAME 2^40,41 trials were an angiogram stenosis of visual moderate severity for which FFR was measured. Many other patients without visual moderate stenosis on angiogram had FFR measurements but were excluded from the FAME trials. For all patients, including those with no significant visual stenosis on angiogram, FFR versus percent DS values are plotted in Fig. 34–18.⁵¹

The blue region shows concordance of severe percent DS with low FFR. However, it also indicates that FFR is not a stand-alone measure of severity. Rather, the validity of FFR to guide PCI depends on a visually moderate angiographic stenosis (ie, it depends on the angiogram). Patients in the red region of Fig. 34–18 had low FFR despite having visually mild or no stenosis on angiogram, likely as a result, in part, to diffuse disease proximal to the pressure wire measurement or preserved CFR with high stress perfusion causing low FFR. In either case, the low FFR may not indicate PCI for either diffuse disease or the non–flow-limiting stenosis. Patients in the yellow region had severe stenosis on angiogram with high FFR, likely the result of diffuse or small-vessel disease or blood caffeine that impaired coronary flow sufficiently to prevent a pressure gradient across the stenosis. This study reported an overall discordance of 35% between FFR and percent DS on angiogram separately from the limitations of resolution on quantitative angiographic analysis.

Thirty-four years ago, angiographic stenosis dimensions were first used to predict physiologic characteristics of stenosis in an in vivo experimental model. Good average correlations between pressure gradients and CFR were found using relatively simple fluid dynamic equations. However, the standard deviation or variability around the good mean correlations was sufficiently great to preclude reliable application to individuals. The most recent advanced technology using computed tomography (CT) angiograms and advanced computational fluid dynamics have also shown a comparable good (but not better) average correlation between CT-predicted FFR and FFR measured by pressure wire.

However, the wide standard deviation about this average good correlation is the same as the early years,^32,34,52.53 which limits application to individuals for personalized clinical management, as illustrated in Fig. 34–19.^34,52 The Bland Altman analysis shows two standard deviations of ± 0.23 for 95% confidence intervals. Therefore, for a true measured FFR of 0.8, the FFR_ct could be 0.57 or 1.0, thereby explaining why the clinical trial of FFR_ct failed to achieve its target of predicting measured FFR.⁵² The reasons include the limited resolution of CT³⁴ and real biological discordance between FFR and CFR.^25,33

Exercise stress testing is embedded in cardiovascular medicine, particularly the Bruce treadmill protocol. Although the diagnostic sensitivity and specificity of ECG changes may be suboptimal, treadmill duration reflecting overall cardiovascular fitness associates with risk of clinically manifest cardiovascular disease, as reviewed below. However, as a currently used component of randomized intervention trials, it does not identify patients for whom revascularization reduces myocardial infarction risk or mortality.^{3,4,5,6,7,8,9,10,11,12,13} Consequently, the relation of exercise capacity to coronary blood flow projects directly into the definition of ischemia, anatomic versus physiologic severity, and their relative risks and treatment outcomes.

A basic limitation is lack of adequate data on quantitative myocardial perfusion during the most commonly used upright treadmill exercise, which precludes acquiring accurate arterial input and quantitative myocardial radionuclide uptake during exercise. Although substantially different exercise stress than the treadmill, supine exercise and dobutamine stress provide some limited insights into associated coronary blood flow. Recent reviews relate myocardial perfusion by quantitative PET using oxygen-15 water to heart rate (HR), mean arterial pressure (MAP), their pressure rate product (PRP), and associated estimated metabolic equivalents (METs) during supine bicycle exercise in healthy young conditioned volunteers.^54,55,56 At severe-to-maximal effort with regard to the anaerobic threshold, HR was over 200 beats/min, MAP was approximately 120 mm Hg, PRP was approximately 20,000, and the myocardial perfusion was approximately 3.0 cc/min/g.

Although normalizing perfusion to PRP is not useful clinically, it serves here for estimating the maximum or ischemic perfusion threshold at high PRP workloads. As reported above,^54,55,56 normalizing perfusion of 3.0 cc/min/g to 20,000 PRP is 0.15 cc/min/g per 1000 PRP units in the healthy young volunteers.⁵⁴ For a convenient MAP of 100 mm Hg and HR of 60 beats/min,⁵⁴ this maximum perfusion threshold is 0.15 × 6 or 0.9 cc/min/g per 6000 PRP units. This threshold of 0.9 cc/min/g per 6000 PRP in healthy young conditioned volunteers establishes their limit of coronary blood flow at their limit of cardiac performance. In patients with CAD, the low-flow perfusion threshold associated with angina and significant ST-segment depression is also 0.9 cc/min/g at PRP of 6000 (MAP 100 mm Hg, HR 60 beats/min).²⁷ Therefore, patients with CAD are limited to much lower PRP workloads at the ischemia threshold of 0.9 cc/min/g at 6000 PRP,²⁷ which is the same threshold of 0.9 cc/min/g per 6000 PRP units for healthy young volunteers who achieve much higher PRP workload at maximum exercise effort.⁵⁴

Therefore, patients with CAD during dipyridamole stress had angina, significant ECG changes, and severe regional perfusion defects at the same threshold, 0.9 cc/min/g per 6000 PRP,²⁷ as healthy young volunteers at maximum exercise limits and PRP of 20,000.⁵⁴ This stress perfusion threshold in these clinical patients was the same for those with total occlusion and myocardial steal, as for those with severe stenosis without total occlusion and no myocardial steal regardless of beta-blockers or other medications. Therefore, at whatever level of effort or PRP causing ischemia in patients or limiting cardiac performance in healthy young subjects, the normalized perfusion threshold appears to be 0.9 cc/min/g per 6000 PRP. A stress perfusion at this threshold or less will likely be associated with angina or ST-segment changes in patients with CAD or associated with maximum cardiac performance in healthy subjects.

However, PRP is not a complete measure of coronary blood flow demand because it does not account for “contractility” that, however, has no standardized definition or quantitative measure. “Contractility” usually parallels HR and blood pressure; thus, PRP remains a useful clinical approximation of metabolic and, therefore, coronary blood flow demand. Myocardial oxygen consumption is a more complete measure of myocardial demand accounting for “contractility” but is not readily measured routinely. Because of the high oxygen extraction from coronary artery blood, coronary blood flow closely parallels oxygen demand and supply, thereby explaining, in part, the concept of a universal absolute perfusion threshold at which ischemia develops or maximal myocardial performance is reached. Finally, in patients, the area under the curve (AUC) of 0.98 for the threshold of 0.9 cc/min/g to predict angina and significant ST-segment changes was not increased or improved by normalizing for PRP. Consequently, this threshold appears to be the observed universal threshold of myocardial perfusion below which ischemia develops or the limits of myocardial performance is reached.

Normalizing perfusion to PRP allows comparison of the perfusion threshold of ischemia or maximum cardiac performance at markedly different workloads, thereby minimizing differences among subjects; it therefore eliminates personalized clinical assessment for any specific single subject. Consequently, primary perfusion data without normalization to PRP are essential for assessing an individual’s coronary flow capacity for personalized clinical decisions.

Ischemic Thresholds and Exercise Pressure Rate Product

This observation thrusts coronary blood flow and exercise into varied conflicting definitions of ischemia best clarified by illustrative case examples. Consider a patient reaching PRP of 20,000 or higher at nine METs⁵⁴ and stage 4 of the Bruce treadmill protocol before getting angina and ST-segment changes on ECG. Although diagnostic of ischemia and CAD, the good cardiovascular capacity associates with relatively low risk of adverse events with medical treatment.⁵⁷ Now consider a patient reaching PRP of 6000 at one METs in stage 1 of the Bruce treadmill protocol or dipyridamole stress with angina and ST-segment changes on ECG; this patient is at high risk for adverse events.⁵⁷ Based on clinical data above, both patients likely have ischemia at the same normalized threshold of 0.9 cc/min/g per 6000 PRP but at markedly different exercise levels.

Although in one sense a universal physiologic measure of ischemia, this normalized perfusion threshold does not indicate the effort level for each patient at which such low perfusion causes ischemia. Ischemia at 20,000 PRP, nine METs, and stage 4 of the Bruce protocol is low risk, whereas ischemia at 6000 PRP,⁵⁷ one MET, and stage 1 of the Bruce protocol is high risk.⁵⁴ However, stress perfusion for the first patient above is high, well over the threshold causing angina and ECG changes during stress perfusion imaging and well over flows associated with high risk. Stress perfusion for the second patient is at the low-flow threshold that is associated with high risk. Thus, stress perfusion of 0.9 cc/min/g becomes an objective, quantitative, universal measure of high-risk ischemia by whatever stress is used.

Both of the above examples have ischemia, but the term fails to provide management direction. Moreover, for clinical practice and intervention trials, treadmill tests are largely viewed as positive or negative for ECG changes or angina. Treadmill duration is less often considered because variability is in part caused by many other factors, particularly deconditioning and musculoskeletal limitations or beta blockade that limits duration aside from restricted coronary blood flow, limiting exercise capacity.

Figure 34–20 shows a graph of this concept with stress flow in cc/min/g and CFR on the vertical axis and PRP on the horizontal axis derived from a large patient database^25,27,28 and the literature.⁵⁴ The large bold Xs in the graphs are measured thresholds of CFR and stress perfusion at which angina and significant ST-segment change developed during dipyridamole stress perfusion imaging. The measured thresholds of stress flow and CFR for patients with total coronary occlusion with myocardial steal are similar to those with severe stenosis without occlusion, averaging 0.9 cc/min/g and CFR 1.4 at an average PRP of 21,000, and a normalized PRP of 0.26 cc/min/g per 6000 PRP. The solid lines plot projected stress flow and CFR at other levels of PRP based on the measured PRP for the patients having angina and ST-segment changes at the observed CFR stress flow thresholds.

The graph shows many different thresholds of stress perfusion or CFR for ischemia depending of the PRP demand. The choice or definition of ischemic flow threshold depends on what question is asked for what purpose. For diagnosis of CAD in active people, a stress threshold of 1.3 to 1.5 cc/min/g or higher and CFR of 2.0 or higher at a high PRP might be observed, but does not associate with high risk,^26,48,49 and therefore is best treated medically.^2,3,4,5,6,7 Thus, ischemia is not necessarily synonymous with high-risk severity indicating revascularization. For quantifying severe high-risk CAD to guide revascularization, a flow threshold of 0.9 cc/min/g or below and CFR of 1.7 or below are documented critical thresholds for angina and ST-segment depression during dipyridamole stress.^{25,26,27,28,29} However, randomized revascularization trials using patient selection based on integrated quantitative stress perfusion and CFR are needed to identify and assess more physiologically severe disease than assessed in current trials.²⁶

In the original report of these thresholds for stress perfusion and CFR at which angina and ST-segment developed,²⁷ normalizing the observed values by the corresponding PRP values did not improve the area under the probability curve separating the patients with and without angina and ECG changes. Because normalization of flows to PRP eliminates its value for assessing severity in an individual, as explained above, the observed 0.9 cc/min/g and CFR 1.7 at which angina and ST-segment changes occurred during stress perfusion imaging are essentially objective quantitative, universal thresholds defining high-risk ischemia that may benefit from invasive procedures. Less severe stress abnormalities indicate reduced stress flow or CFR but not ischemic high-risk, low coronary flow capacity.

With low rest flow and low stress flow resulting from beta blockade with adequate CFR, patients usually have no angina or ST-segment change with exercise despite very low stress flow. This reduced flow demand parallels reduced myocardial oxygen demand and reduced PRP at a given level of exercise that is the mechanism of beta-blocker relief of angina. With beta blockade, stress perfusion may be low because of low PRP for a given level of exercise and remaining CFR. As exercise intensity increases, this remaining CFR may be recruited until reaching the threshold of 0.9 cc/min/g per 6000 PRP units when angina and ST-segment changes are likely to develop, limiting further exertion.

Therefore, with beta blockade in patients with CAD, CFR provides additional diagnostic insight over and above stress perfusion alone to help guide management. Patients with CAD on beta-blockers commonly have low stress perfusion but remaining CFR associated with no angina or ST-segment changes at dipyridamole or exercise stress. Therefore, there is little basis for revascularization in such asymptomatic patients because revascularization trials show no reduction in rate of myocardial infarction or death.^{1,2,3,4,5,6,7,8} However, if CFR is also low, below 1.7, the combined low CFR and low stress perfusion associate with severe CAD and high-risk angina and ST depression with stress, for which revascularization may reduce adverse outcomes,⁴⁹ although this concept remains unproven in randomized trials.

Traditionally, diagnostic testing identifies CAD by symptoms, a relative perfusion defect, quantitative CFR of < 2.0 or FFR ≤ 0.8 to guide revascularization. However, such arbitrary thresholds have not correlated with reduced rates of myocardial infarction or death after revascularization in randomized trials. Consequently, an essential goal of quantitative myocardial perfusion imaging is to identify patients with sufficiently physiologic severity incurring sufficiently high risk that revascularization reduces rates of myocardial infarction or death as an alternative goal in addition to angina relief.

Exercise, Coronary Blood Flow, and Type 2 Supply/Demand Myocardial Infarction

ACS during or within 1 hour of exercise is rare, occurring in 4% to 10% of ACS cases, with highest prevalence in deconditioned subjects not doing regular exercise.⁵⁸ Even in this small percent of patients, ACS during exercise is not likely a simple supply/demand imbalance, for several reasons. For fixed stable structural narrowing, habitual exercise would be expected to increase the frequency of exercise-induced ACS. However, in fact, risk of ACS during exercise decreases with increased exercise frequency.⁵⁸ Therefore, ACS during exercise on a given day implies underlying progression, plaque disruption, sympathetic vasoconstriction, thrombosis associated with increased blood pressure, and tachycardia enhanced by sympathetic activity. Hence, the vast majority of ACS is driven by low flow caused by severe narrowing, while the very small minority is driven by demand that exceeds significant flow-limiting stenosis. Undoubtedly, demand ischemia may cause arrhythmia and sudden cardiac death. However, there is strong evidence that benefits of exercise far override the small risk of incurring ACS during exercise.⁵⁸

Lack of specific meaning of the term ischemia addressed earlier in this chapter also characterizes subcategories of myocardial infarction. In a 2014 review,⁵⁹ a type 1 myocardial infarction was defined as “secondary to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus leading to decreased myocardial blood flow or distal platelet emboli with consequent myocyte necrosis (ACS).” A type 2 myocardial infarction was defined as “due to supply/demand mismatch, without plaque rupture, but also with myocardial necrosis evidenced by a rise and/or fall of cardiac biomarkers either … in addition to at least one of the other criteria for MI.”⁵⁹ However, the authors note that “several major expert opinion documents have provided some guidance ... but none of these documents have defined specific criteria for [type 2 myocardial infarction]” and state that “the current ‘gold-standard’ definition for [type 2 myocardial infarction] remains undetermined”⁵⁹

The review continues, “On the basis of the above criteria, [type 2 myocardial infarction] is diagnosed in instances in which a supply/demand imbalance leads to myocardial injury with necrosis that is not caused by ACS, including arrhythmias, aortic dissection, severe aortic valve disease, hypertrophic cardiomyopathy, shock, respiratory failure, severe anemia, hypertension with or without left ventricular hypertrophy, coronary spasm, coronary embolism or vasculitis, and coronary endothelial dysfunction without significant coronary artery disease.”⁵⁹ The term STEMI correlates with type 1 myocardial infarction, whereas NSTEMI correlates with type 2 myocardial infarction.⁵⁹

These fine type 1 and type 2 distinctions have become even more blurred for several reasons. First, as reviewed earlier in this chapter, OCT-IVUS studies of ACS show, on average, severe stenosis of 72% diameter narrowing with complex morphology^16,17,18,19 not fitting any single pathophysiology corresponding to the type 1 and type 2 myocardial infarction categories. Second, pathology in people who died from myocardial infarction shows that about 90% had serial small plaque ruptures that healed, leading to severe stenosis that lowered flow enough to cause infarction or a final plaque rupture or thrombosis occluding the stenosis.¹⁵ Third, frequently elevated high-sensitivity troponin levels found with no ECG, functional, or clinical evidence of myocardial infarction further cloud the definitions, meaning, implications, future risk, and treatment. Fourth, trials of revascularization for ACS have reduced rates of myocardial infarction and death irrespective of these fine distinctions.

Finally, even for the above definitions of type 2 myocardial infarction, exercise-demand myocardial infarction is very uncommon compared to the vast proportion of coronary events occurring at rest, during sleep, or during minimal activity.^58,59 Therefore, the essential basis for coronary events is low coronary flow caused by severe stenosis, not supply/demand imbalance during exercise. As in the review quoted above, a major criteria of type 2 myocardial infarction is absence of “significant coronary artery disease.”⁵⁹ Of course, other pathologies causing myocardial infarction, as listed above, may constitute the true uncommon supply/demand imbalance without flow-limiting stenosis or diffuse CAD. However, of such cases, the problem is nearly always an excess demand in the face of underlying moderate-to-severe CAD, so that the proportional contribution of demand versus flow-limiting disease severity is moot and of little clinical or conceptual importance.

Quantitative myocardial perfusion provides a universal cohesive integrated view of the continuous spectrum of coronary events, such as OCT-IVUS and pathology, thereby avoiding artificial binary classifications that have proven poor guides to revascularization decisions. The threshold of stress flow at 0.9 cc/min/g and CFR of 1.7 associated with angina and significant ST-segment depression during dipyridamole stress serve as a nearly universal measure of critical severity because the vast majority of acute coronary events occur during resting conditions or minimal activity for the wide mixed spectrum of pathologies reducing coronary blood flow.

Coronary blood flow and myocardial perfusion may be substantially heterogeneous, both globally and regionally and over time; the causes are normal, pathologic, or iatrogenic mechanisms that are multiple, complex, or interacting. Rather than viewed as an important useful insight into coronary pathophysiology, this heterogeneity is commonly viewed as a “diagnostic limitation” of methodology or biological variability, or competing diagnostic value of relative perfusion abnormalities versus CFR versus stress perfusion versus exercise or pharmacologic stress. However, the reality of heterogeneous rest and stress perfusion requires incorporation of all of these measurements in order to quantify the wide range of complex coronary pathophysiology essential for individualized management decisions.

Rather than ignoring or selectively excluding such heterogeneity from clinical perfusion displays, quantitative data, or clinical interpretation, we account for and incorporate it into our image display as important physiologic information essential for optimal clinical value. Figure 34–21²⁸ illustrates the complex data inherent in all quantitative perfusion imaging. This complexity is then integrated into a “simple” easily understood image for clinical decisions by validated directive software based on a large patient database, further detailed in the chapter on PET imaging (Chap. 19). In Fig. 34–21, panel A displays relative myocardial perfusion images of rubidium-82 at rest and during dipyridamole stress. With the arterial input function for rest and stress (not shown), panel B displays rest and stress perfusion in cc/min/g and CFR for every pixel in every topographic image in each of four views of the human schematic figure. The CFR and stress perfusion for each pixel is then plotted on the graph with CFR on the vertical axis and stress perfusion on the horizontal axis in panel C.

The color codes correspond to clinical status of 1876 patients grouped according clinical status and CFR and stress perfusion in cc/min/g.^{24,25,27,28,60} Red codes 125 young healthy volunteers under 40 years of age without risk factors or blood caffeine.⁶⁰ Blue codes patients having angina, ECG changes, and/or a regional stress defect during dipyridamole stress PET imaging. Green codes for patients with either angina or ECG changes but not both during stress imaging. Orange codes for patients with CFR and stress flow at the lower one standard deviation of the healthy volunteers. Yellow codes for the upper one standard deviation above the patients with angina or ST-segment changes during stress imaging. The orange-to-yellow transition is halfway between these standard deviation limits. As documented in the chapter on PET imaging (Chap. 19), the color codes correspond to healthy young volunteers (red), patients with risk factors without known CAD (orange), patients with documented CAD with and without revascularization (yellow), patients with angina and/or ECG changes during dipyridamole stress as above (blue or green) and patients with myocardial steal (dark blue).^{24,25,27,28,60}

Each color-coded pixel is then mapped to its original position and displayed as the coronary flow capacity map in four projections (lateral, inferior, septal, and anterior views) within the generic distribution of the coronary arteries as seen in panel D. For this patient’s coronary flow capacity map, there is a small severe distal stress defect in the distribution of a small distal diagonal branch with myocardial steal associated with collaterals beyond an occlusion. The left anterior descending coronary artery (LAD) distribution has good proximal CFR and stress flow (orange) tapering to mildly reduce levels (yellow) distally caused by diffuse disease without flow-limiting stenosis in the LAD distribution itself. Adjacent is the severe stress defect (blue) caused by the small occluded distal diagonal. The left circumflex and right coronary artery distributions have the best coronary flow capacity (red). The angiogram inset (in panel E) confirmed all of these conclusions made from the coronary flow capacity map prior to angiogram.

Therefore, the easily understood, “simple” directive flow capacity map accounted for and integrated regionally complex heterogeneous perfusion data that are not readily interpreted from the primary perfusion displays. The coronary flow capacity map also provides an objective measure of percent of the left ventricle within each range of CFR and stress flow as a reflection of the LV mass at risk. A region comprising 15% of the left ventricle with stress flow at 0.9 cc/min/g and CFR at or below 1.7 may be a reasonable size threshold for revascularization based on the observation that the ejection fraction starts to decrease and be associated with adverse prognosis when an infarct covers 23% or more of the left ventricle⁶¹ and the CFR threshold of 1.5 is associated with adverse coronary events.^48,49

Figure 34–22 shows two topographic views of three common patterns of quantitative myocardial perfusion for which either CFR or stress perfusion alone fails to provide the needed definitive information for clinical management that is provided by both together. For efficiency of comparisons, only two of the four topographic views are displayed. In panel A, rest perfusion (first row) is very high, stress perfusion also high (second row) and CFR very low (third row) because of the high rest flow, as commonly seen with anxiety, high blood pressure, and in women. In panel B, rest perfusion is very low because of beta-blockers; stress flow is also low but CFR is excellent and well above the ischemic threshold.

For both cases A and B, the integrated coronary flow capacity map (fourth row) of Fig. 34–22 accounts for both CFR and stress perfusion scaled according to the color bar for both CFR and stress perfusion together. For these two examples, the red regions indicate coronary flow capacity of young, healthy volunteers without risk factors. With such common global perfusion heterogeneity, CFR alone or stress perfusion alone fails to characterize adequately the coronary blood flow of these examples as the basis of clinical management.

In panel C, the absolute rest and stress perfusion images in cc/min/g are so diffusely reduced as to preclude visual differentiation of scar from low rest or stress perfusion. However, the CFR display and the coronary flow capacity map all show fixed scar as well as reduced, but adequate, (orange and yellow) perfusion outside the scar on the coronary flow capacity map. The coronary flow capacity map also scales perfusion for less than or equal 0.2 cc/min/g from the resting image as scar indicated by the hatched area within the low-flow blue zone. As detailed in Fig. 34–21, the red to orange to yellow to green to blue regions correspond to progressive lower combinations of reduced CFR and stress perfusion in 1876 patients, as per the color bar beside the coronary flow capacity map.

Although they both quantify physiologic severity, CFR and stress perfusion are independent and complimentary, and both are necessary for definitive complete definition of severity. Stress perfusion alone fails to assess severity adequately in several common clinical circumstances. Stress perfusion alone cannot distinguish myocardial scar from a stress-induced perfusion defect or identify myocardial steal associated with collaterals, both of which require CFR or the resting image. Beta blockade may profoundly lower the stress flow to below the low-flow threshold that would cause angina or ECG changes without beta-blockers. This lowered threshold by beta blockade prevents angina or ECG changes at much lower stress flow than without beta-blockers. Such patients usually have very low stress perfusion, but also low rest perfusion, with resulting good CFR that prevents ischemia with activity.

CFR alone also fails to quantify severity when rest flow is high resulting from hypertension, anxiety, or gender with adequate stress perfusion and corresponding low CFR that causes no ischemia resulting from adequate stress perfusion. Thus, quantitative rest and stress perfusion and CFR are all needed, integrated into the coronary flow capacity map in order to define common clinical conditions. Integrated quantitative perfusion identifies and quantifies diverse components of myocardial scar with ischemic border zones, cardiomyopathy with low ejection fraction particularly with CAD, hibernating myocardium, diffuse CAD, mixed focal plus diffuse disease, endothelial dysfunction, caffeine nonresponders, beta blockade or other drugs that alter or lower stress flow, postprocedure patients, and occlusions with myocardial steal.

Although we use quantitative PET perfusion images to illustrate this essential clinical pathophysiology, any other technology providing corresponding CFR and absolute coronary flow documents the concepts. For example, Fig. 34–23 shows invasive measures of coronary flow capacity using intracoronary flow velocity wires during pharmacologic stress.⁶² Coronary flow velocity reserve is plotted on the vertical axis with hyperemic flow velocity on the horizontal axis in panel A. The colors code for normal, mildly reduced and moderately reduced coronary flow capacity associated with risk of MACE in panel B. Although other technologies of MRI and CT perfusion may eventually provide such comprehensive physiologic data, PET remains optimal with the largest supportive literature and experience.^{24,25,26,27,28,29,33,34,48,49,50,54,55,56,60,61}

Figs. 34–3, 34–7, and Fig. 34–15 above indicate the essential component of diffuse CAD underlying most stenosis that carries high risk of adverse events that remains after revascularization. In the Surgical Treatment for Ischemic Heart Failure (STICH) trial, CAB in three-vessel disease failed to lower mortality.^6,7 In meta-analysis of FFR-guided PCI, residual FFR after successful PCI is associated with subsequent risk of recurrent MACE.⁴⁴ In Fig. 34–24, the severe abnormality on the coronary flow capacity map of panel A, on the same patient as in Fig. 34–14, improved after successful PCI (see panel B). However, the residual mildly and diffusely reduced coronary flow capacity (yellow) in panel B indicates substantial diffuse remaining disease not seen on the angiogram but requiring intense medical management in order to prevent further progression, cause regression,^63,64 and reduce adverse events.^65,66 Failure to account for or quantify diffuse disease in randomized revascularization trials explains, in part, failure to reduce myocardial infarction rate or mortality resulting from residual diffuse disease.²⁶

CAD in women is characterized by atypical chest pain, diffuse epicardial coronary atherosclerosis, microvascular dysfunction, inaccurate diagnostic tests, delayed or late ACS associated with high mortality, and differential responses to medical treatment or invasive procedures in women compared to men.^67,68 Although these differences are well described and likely related to hormonal influences, they remain without a systematic mechanistic explanation. However, coronary blood flow and associated fluid dynamics offer some insight into potential mechanisms as recently reported and summarized in Fig. 34–25.⁶⁹

Coronary arteries in women are smaller than men,^70,71,72 but myocardial perfusion is higher in women.⁶¹ Accordingly, average endothelial shear is higher in women.^61,64 High endothelial shear stress inhibits low-density lipoprotein transport by reducing “leaky” endothelial cell junctions; inhibiting inflammation, platelet activation, and thrombosis; retarding oxidative processes; promoting mild stable uniform remodeling; and inhibiting focal atheroma, focal stenosis, and plaque instability.^{69,73,74,75,76,77,78} These beneficial effects are mediated by high shear that upregulates endothelial nitric oxide (NO), NO synthase (eNOS) gene expression, eNOS phosphorylation, manganese superoxide dismutase expression and downregulates endothelial NADPH oxidase, thereby decreasing superoxide ion and oxidative stress.^{73,74,75,76,77,78} The later section on pressure-flow relationships reviews the fluid dynamic equations describing the arterial size, length, and regional LV mass relations that define the structure of the branching coronary artery tree for women compared to men.

These beneficial effects of high endothelial shear on inhibiting atheroma formation applied throughout the coronary artery tree of women may explain their average different manifestation of CAD. However, endothelial shear stress and its effects are a complex, heterogeneously varying regional, time-and age-related continuum with great individual differences. Consequently, for given risk factors, some women never get CAD, other develop it prematurely like men, others have delayed focal disease, and commonly, in women, coronary atherosclerosis is modified by high shear into diffuse disease without focal stenosis.

Shear effects on CAD in women may also explain their frequent atypical nonexertional angina because of diffuse coronary narrowing that relates linearly with flow (flow¹), thereby causing less pressure gradient, less subendocardial ischemia and less angina with exercise.⁶⁹ In contrast, with more focal stenosis in men, increased coronary flow with exercise associates with a stenosis pressure gradient proportional to flow raised to the second power (flow²), thereby reducing coronary perfusion pressure with consequent subendocardial under perfusion and angina.

Late stenosis in women is superimposed on severe diffuse disease developing silently over their middle years to produce a large burden of atherosclerosis in small arteries that incurs higher risk than men who present earlier in life with primarily focal disease. With estrogen withdrawal, the partial protection of their high shear stress against atheroma formation is lost, leading to “accelerated” clinical manifestations caused by focal stenosis added to diffuse disease. The long “silent” period of developing diffuse coronary atherosclerosis in women may evolve a more lethal combination of diffuse plus late focal disease than commonly seen in men. Therefore, vigorous risk factor treatment is essential during this long latent period in order to reduce adverse outcomes.

Having established the relevance of coronary blood flow and pathophysiology to clinical cardiology, let us now review other clinically pertinent aspects of coronary blood flow. Figure 34–26 shows recordings of coronary blood flow velocity, aortic and coronary pressures, and the coronary pressure gradient at resting conditions without stenosis (panel A), with moderate stenosis (panel B), and with severe stenosis (panel C) in a chronically instrumented canine model of coronary artery stenosis.⁷⁹ With no stenosis, systolic compression reduces systolic coronary flow. During isometric LV contraction in early systole, coronary pressure rises above aortic pressure because of a momentary reversal of the aortic gradient to negative values (red arrow) arising from the pressure wave caused by isometric contraction propagating backward through the coronary arteries before the aortic valve opens. For the moderate stenosis in (B), this reversed gradient with coronary pressure higher than aortic pressure in early systole is replaced by varying pressure gradient from zero in early systole at zero flow to 38 mm Hg during the maximum early diastolic flow. The phasic flow is more damped with the peak diastolic flow reduced.

At the severe stenosis in C, the phasic pressure gradient reaches 40 to 50 mm Hg while average rest flow velocity remains normal. However, the phasic pattern of coronary flow is lost with increased coronary flow during systole compared to low systolic flow in the absence of stenosis. This paradoxical increased coronary flow with severe stenosis is caused by the loss of regional systolic compression associated with the low coronary perfusion pressure and consequent subendocardial underperfusion and ischemia.

Figure 34–27 shows the same experimental stenosis model with a mild-to-moderate stenosis at resting baseline conditions in panel A with systolic compression reducing systolic flow and the momentary reversal of coronary pressure or aortic pressure during isometric systole.⁷⁹ With progressive vasodilation stress in panels B, C, and D, mean coronary flow velocity increases only modestly as the pressure gradient increases proportionately much more. The phasic pattern of coronary flow is damped with increased systolic flow compared to low systolic flow without stenosis. Thus, the phasic pattern of coronary blood flow during vasodilator stress parallels the phasic flow changes during progressive stenosis at resting conditions.

Figure 34–28 plots the phasic pressure gradient and flow velocities during a single cardiac cycle for a mild stenosis.⁷⁹ The highlighted regions of the phasic tracings and the dashed lines of the pressure-flow plot show the systolic deceleration and early diastolic acceleration of flow that distort the smooth diastolic pressure gradient flow relation fitting a characteristic quadratic fluid dynamic equation equation.⁷⁹ Deceleration or stopping coronary blood flow by systolic compression and early diastolic acceleration of coronary blood flow at high early diastolic pressure are associated with inertial pressure loss separately and independently from the pure diastolic pressure-flow characteristics of the stenosis.

Consequently, average coronary pressure gradient flow relations are somewhat different from the pure diastolic pressure gradient relations undistorted by systolic compression of the coronary vascular bed.

The schematic in Fig. 34–29 shows the fluid dynamic equations relating stenosis dimensions, coronary blood flow, pressure gradient, flow profiles, exit vortex shedding, and endothelial shear stress. The quadratic equation has a viscous pressure loss linearly proportional to flow and an exit separation loss proportional to flow squared. Both viscous and separation pressure losses are related to the arterial radius raised to the fourth power. Consequently, small changes in arterial diameter that are not visible or quantifiable on angiogram may have major effects on coronary flow or CFR incurring high or low risk. Figure 34–30 lists the consequences of the flow profile patterns on biologic behavior of the atherosclerotic coronary artery. High endothelial shear stress has antiatherogenic effects, whereas low shear stress is atherogenic with implications for the different manifestations of CAD in women versus men addressed in the prior section on coronary blood flow in women.

These pressure-flow curves first defined in experimental stenosis⁷⁹ have been confirmed in patients^80,81,82,83 by pressure-flow velocity wires, as in Fig. 34–31, with panel A showing diastolic pressure-flow velocity (p-v) plots fitting the quadratic fluid dynamic equation; panel B showing p-v plots for severe, moderate, and mild stenosis; and panel C showing p-v plots of a severe stenosis before and after PCI.⁸¹ All current invasive and noninvasive quantification of physiologic stenosis severity using FFR and stress perfusion imaging to guide management are based on these experimental models, classical fluid dynamic equations, and early confirmation in patients. The discordances between CFR, FFR, and/or stress perfusion noted above arise from choosing one of these measures alone that inadequately defines the actual physiologic complexity of CAD over the wide range of clinical conditions. Consequently, complete invasive pressure flow relations are currently being acquired in the DEFINE FLOW (Distal Evaluation of Functional performance with Intravascular sensors to assess the Narrowing Effect— Combined pressure and Doppler FLOW velocity measurements) trial to resolve the implications of FFR-CFR discordance for management decisions (ClinicalTrials.gov NCT02328820).

Fluid dynamic equations tell an even more profound story than quantifying coronary artery stenosis clinically. The arterial size, length, and branching tree structure of the mammalian heart can be explained or described by equations derived from three different starting points: (1) minimal energy loss for coronary blood flow distribution, (2) adaptive arterial size to normalize wall shear stress, and (3) parent-to-child branching arterial size for downstream mass.^35,36,72 All three derivations confirm the same equation now validated in clinical and animal studies as follows: arterial cross-sectional area = (K) flow^0.67, where flow is proportional to mass that is proportional to the sum of branch lengths beyond each point along the length of the artery on clinical coronary arteriograms defining K, as in Fig. 34–32A.³⁵

Remarkably, this equation for women is different than for men (Fig 34–32B). Women have smaller arteries and men have larger arteries⁷² than predicted by the original equation derived from both male and female patients in equal proportion.³⁵ The data indicate that women do not adapt to wall shear stress with increased arterial size as much as men. Women thereby maintain higher wall shear stress than men with corresponding antiatherosclerotic benefits summarized in Figs. 34–25 and 34–30. Thus, the mammalian heart of 200 million years ago, coronary blood flow, human gender evolution, fluid dynamic equations, pressure-flow measurements, CFR, FFR, quantitative perfusion imaging, diagnostic tests, CAD in women versus men, and their differential optimal treatment comprise a highly integrated conceptual continuum, a syncytium of knowledge immediately relevant to cardiovascular medicine and patient survival.

After brief 10- to 20-second coronary occlusion, coronary flow increases dramatically for a longer time than the occlusion. This flow response to brief occlusion is called reactive hyperemia, shown in Fig. 34–33A.⁸⁴ The volume of flow repayment is four times greater than the flow deficit during occlusion so that flow repayment to the myocardium is four times the flow debt. Consequently, during coronary reactive hyperemia, the oxygen content of coronary venous blood may double or triple because of unextracted oxygen not needed by the myocardium.

This surplus flow after transient occlusion is far more than needed to repay myocardial flow or oxygen demands, as shown in Fig. 34–33B where the coronary system is perfused with deoxygenated blood for the same time period of occlusion. Flow payback after perfusion with deoxygenated blood exactly matches the flow debt. The excess flow payback after brief occlusion is therefore caused by mechanisms other than oxygen payback, particularly autoregulation, discussed below. Reactive hyperemia occurs after the brief systolic compression of every heart cycle, contributing to the rapid rise in coronary blood flow early in diastole in Figs. 34–26, 34–27, and 34–28.

The factors controlling coronary blood flow include myocardial metabolism, autoregulation, shear-mediated vasodilation, contractile compression, endothelial function, perfusion pressure, and direct or indirect sympathetic and parasympathetic neural mechanisms, as briefly outlined below. Thus, reactive hyperemia reflects all the complex interacting control mechanisms for coronary blood flow optimized for evolutionary survival. It occurs after every systolic contraction and immediately after every balloon deflation at PCI, generally without cognizance of its physiologic significance for coronary blood flow or its profound, elegant, complex, interacting control mechanisms already evolved in the mammalian heart before dinosaurs ruled the earth. The asteroid creating the Chixulub crater and Deccan volcanism ended their rule, thereby making way for this extraordinary pulsatile, self-fueling pump to support mammalian evolution to the mobility, dexterity, and mental capacity for writing this sentence in Hurst’s The Heart some 66 million years later.

Intramyocardial Steal and Subendocardial Ischemia

Intramyocardial steal, also called subendocardial-subepicardial steal, is common, manifest as stress-induced ST-segment depression on ECG and usually angina with reduced average transmural perfusion in cc/min/g to the ischemic threshold of 0.9 cc/min/g. It results from several interacting mechanisms, revealing profound insights into the exquisite regional control of coronary blood flow by ATP release from red blood cells in local regions of myocardial hypoxia in response to delayed subendocardial hyperemia by stenosis and fall in coronary pressure associated with increased flow during vasodilator stress.

Delayed Subendocardial Hyperemia

As listed in Table 34–1, the subendocardium has higher wall tension then the subepicardium and consequently greater oxygen demands. Compared to the subepicardium, the subendocardial perfusion is limited by systolic compression, lower perfusion pressure, greater diastolic tissue pressure, and longer perfusion distances compared to subepicardium. Consequently, subendocardial arterioles are more dilated and more capillaries are recruited with less remaining vasodilatory reserve, oxygen extraction is greater with lower tissue pO₂, lower ATP levels, potential lactate production rather than utilization, and lower saturation of coronary venous blood.

The normal reactive hyperemia after systolic compression with rapid rise in early diastolic flow is delayed to the subendocardium, as seen in Fig. 34–34.⁸⁵ Even a delay of a few seconds during tachycardia further compromises subendocardial perfusion. Coronary artery stenosis further impairs the early rapid diastolic perfusion to subendocardium, especially with tachycardia, thereby explaining subendocardial ischemia and ST-segment depression during exercise tachycardia. Similarly, LV hypertrophy with a thickened LV wall, especially aortic stenosis, impairs rapid diastolic perfusion to subendocardium during tachycardia even without coronary stenosis.

Low Coronary Pressure Caused by Increased Flow during Vasodilator Stress

As flow increases through a stenosis, the pressure gradient increases and distal coronary pressure falls, thereby impairing subendocardial perfusion more than the subepicardium. As in Fig. 34–35, myocardial perfusion is relatively well maintained at coronary perfusion pressures down to 37 to 40 mm Hg.⁸⁶ However, as perfusion pressure falls further to 28 mm Hg, subendocardial perfusion falls by 50% or more while subepicardial perfusion is maintained. This subepicardial to subendocardial perfusion gradient is called intramyocardial steal because of the superficial appearance of perfusion being “stolen away” from the subendocardium by the subepicardium. However, the term is a misnomer because blood flow is not withdrawn from one region by another region. The intramyocardial gradient is caused by subendocardial perfusion falling more than subepicardial perfusion at low perfusion pressures. Figure 34–36⁸⁷ shows preservation of contractile function at a perfusion pressure of 38 mm Hg in an experimental model consistent with Fig. 34–35 relating perfusion pressure and subendocardial perfusion.

Why Does Remaining Coronary Flow Reserve with Severe Stenosis Lower Resting Coronary Blood Flow?

Counterintuitively, coronary flow increases with vasodilator stress even after severe stenosis reduces resting coronary blood flow, as first reported in 1975.⁸⁸ Holding back this potential increased reserve flow capacity that maintains adequate perfusion pressure appears superficially to be an astonishing teleological adaptation for maintaining subendocardial perfusion. However, in reality, the explanation is not teleological intelligence of the coronary arteries but rather their exquisite regional control of coronary blood flow by ATP release from red blood cells in a hypoxic environment, as detailed in the next section of control mechanisms for coronary blood flow. As epicardial perfusion pressure and flow fall because of stenosis, the subendocardium vasodilates maximally as a result of ATP release from red blood cells that prevents ischemia up to a limit. At that level of epicardial perfusion pressure and flow, the subepicardium sees higher pressure and flow, thereby not vasodilating maximally.

With added pharmacologic vasodilator stress, the epicardial flow increases, the pressure gradient across the stenosis increases, and perfusion pressure falls, thereby making the subendocardium ischemic. With pharmacologic arteriolar vasodilation distal to a stenosis with increase transmural perfusion, paradoxically subendocardial perfusion falls with ischemia as epicardial coronary blood flow increases—hence the misnomer intramyocardial steal. Reversing the vasodilator stress or beta blockade lowers epicardial coronary artery flow, lowers the pressure gradient, increases perfusion pressure, and relieves subendocardial ischemia. Thus, with severe stenosis lowering resting flow, the remaining coronary flow reserve is regional subepicardial flow reserve that has no stimulus for vasodilation because it has adequate pressure and perfusion.

Figures 34–37 and 34–38 demonstrate this subendocardial hypoperfusion during vasodilatory stress with progressive coronary artery stenosis in the first images of subendocardial underperfusion in an experimental model with postmortem imaging of cross-sectional LV slices before availability of in vivo tomographic myocardial perfusion imaging.⁸⁹ Even mild stenosis caused reduced subendocardial stress perfusion during vasodilator stress. With more severe stenosis, the stress perfusion abnormality extends transmurally. Earlier sections of this chapter establish that severely reduced average transmural perfusion associates with high risk of adverse events but mild-to-moderately reduced average transmural perfusion does not associate with high risk of adverse events. Consequently, the subtle milder subendocardial perfusion during stress caused by mild-to-moderate stenosis may establish a diagnosis but may not justify interventions in the absence of severe large transmural stress perfusion defects.

Does Intramyocardial Steal Negate the Observed Average Transmural Threshold for Ischemia of 0.9 cc/min/g?

The average transmural perfusion of 0.9 cc/min/g associated with angina and ST-segment depression on ECG is a hard clinical correlation with severe epicardial stenosis. This average transmural threshold reflects a lower subendocardial and higher subepicardial perfusion than this average with a severe subendocardial-to-subepicardial perfusion gradient. Therefore, intramyocardial steal does not negate the average transmural flow threshold at which ischemia develops, but rather reinforces this threshold at which angina and ST-segment depression reflect subendocardial underperfusion and ischemia. Currently, subendocardial and subepicardial perfusion values are not routinely measured for clinical decisions by any technology. However, even if possible clinically, measuring subendocardial perfusion may not provide any additional critical information over the mean transmural stress perfusion that associates closely with high- or low-risk CAD regardless of subendocardium perfusion. With reduced but adequate mean transmural stress perfusion, subendocardial hypoperfusion may be present, but risk of adverse events is well defined by the mean transmural perfusion, thereby limiting the clinical value of quantifying subendocardial perfusion for clinical decisions.

Collateral Steal

Collateral steal refers to a fall in perfusion below resting levels in a region of myocardium supplied by collaterals beyond an occlusion or severe stenosis during vasodilator stress that increases perfusion in other regions of the left ventricle (Fig. 34–39). It therefore parallels intramural myocardial steal except involves different regional distributions of the coronary arteries rather than an intramural perfusion gradient. Therefore, regional collateral steal can be imaged and quantified during vasodilator stress as indicating collateral perfusion. The pressure-flow mechanisms of collateral steal illustrated in Fig. 34–39 are similar to intramyocardial steal. With even moderate stenosis or mild diffuse CAD of the arteries supplying the collaterals, increased flow in the arteries supplying the collaterals causes the distal perfusion pressure in the supply artery to fall at the origin of the collaterals. This lowered perfusion pressure during vasodilator stress reduces collateral perfusion to below resting perfusion present before vasodilator stress, thereby potentially causing angina and ST-segment depression. The fall in perfusion in the collateralized myocardium as perfusion in surrounding regions increases gives the appearance of the surrounding region “stealing” or shunting blood back out of the collateralized region. However, no such backward shunting occurs. Instead, perfusion in the collateralized area simply falls because of the lowered perfusion pressure resulting from high flows in the supply artery having even mild stenosis or diffuse narrowing. Stopping the vasodilator stress lowers blood flow in the supply artery, decreases the pressure gradient and increases collateral perfusion pressure and flow with relief of angina or ST-segment changes. PET images of collateral steal are shown in the chapter on cardiac PET (Chap. 19).

Branch Steal

The final form of myocardial steal in the absence of collaterals manifests as a base to apex longitudinal perfusion gradient with adequate or high stress perfusion at the base of the left ventricle, tapering to low ischemic perfusion at the apex of the left ventricle associated with angina and ST-segment depression.^90,91 It is seen with severe diffuse three-vessel CAD with diffusely small-lumen arteries without occlusion or severe focal stenosis and without collaterals. The mechanism is falling pressure along the length of the artery as flow increases during vasodilator stress. With this longitudinally falling coronary perfusion pressure, the proximal artery branches have higher perfusion pressure than more distal branches, thereby providing lower resistance proximal localized vascular bed to which flow preferentially goes, thereby decreasing flow to the distal branches. This shunting of blood flow to proximal branches from distal branches is a true steal phenomenon with perfusion at the apex falling below resting levels, thereby causing ischemia. It is also readily imaged by PET, indicating severe diffuse CAD.⁹¹

Myocardial Oxygen Demand and Coronary Blood Flow

Of the many factors affecting coronary blood flow, the primary controller is metabolic demand that nearly instantaneously regulates regional coronary flow, even in small separate myocardial regions independently. Figs. 34–40 and 34–41 define the mechanism.^92,93 Myocardial oxygen demand regulates coronary blood flow via ATP release from oxygenated red blood cells at low myocardial partial oxygen pressure. This ATP acts on microvascular endothelium to cause arteriolar vasodilation and increased regional coronary blood flow. From a chronically instrumented model, plasma ATP in arterial and coronary venous blood correlate tightly with myocardial oxygen consumption during treadmill exercise shown in Fig. 34–40. Coronary blood flow correlates tightly with coronary venous plasma ATP (see Fig. 34–41A) and with the coronary venous-arterial difference in plasma ATP concentration (see Fig. 34–41B).

Autoregulation of Coronary Blood Flow

Coronary arterial smooth muscle inherently responds to changes in arterial pressure even with adequate arterial oxygenation and in the absence of myocardium or neural connections, as seen in Fig. 34–42.⁹⁴ A sudden rise in coronary pressure that initially increases coronary blood flow incurs coronary artery vasoconstriction that reduces flow back toward baseline. A sudden fall in coronary pressure that initially reduces coronary blood flow incurs vasodilation that increases flow back toward baseline. Autoregulation is a major component of reactive hyperemia after systolic contraction and after balloon occlusion at PCI.

Coronary Perfusion Pressure, Coronary Blood Flow, and LV Function

Perfusion pressure in relation to coronary blood flow has been addressed in previous sections on FFR and phasic pressure flow relations. Despite major advances in clinical coronary pathophysiology derived from FFR, the relation of FFR or coronary pressure directly to ischemia manifest as angina, ECG changes or contractile dysfunction remains poorly defined. Because of its invasiveness, the consequences of low FFR are all indirect, remote observations or associations with exercise tests, single-photon emission CT, or PET stress perfusion imaging done at a different time or as outcomes in trials. Although important, such remote associations do not elucidate pathophysiologic effects of low coronary pressure compared to coronary blood flow.

In the experimental model of Fig. 34–36,^25,87 coronary flow was held constant while mean coronary pressure was decreased to an average of 38 mm Hg and an FFR of 0.43 or 43% of normal control pressure, or a 57% fall in perfusion pressure. Contractile function was maintained at perfusion pressure of less than half the normal control pressure. The data indicate that the heart is fairly tolerant of low pressure. By comparison, myocardial steal during dipyridamole stress that reduces resting myocardial perfusion to even 80% of resting levels typically causes angina, ECG changes, and regional dysfunction on ECG-gated perfusion PET images.^27,28 For quantitative PET perfusion imaging, coronary blood flow reduced by 57% below resting levels causes a very severe defect associated with regional contractile dysfunction, angina, and ECG changes not seen with a comparable 57% decrease in perfusion pressure.

Myocardial Compression of Coronary Blood Flow

The phasic pressure flow recordings of Figs. 34–26, 34–27, and 34–28 and the reactive hyperemia of Figs. 34–33 and 34–34 show the effect of systolic compression on coronary blood flow, particularly associated with reduced diastolic perfusion time of tachycardia and limited rapid early rise of diastolic flow caused by coronary artery stenosis or LV hypertrophy.

Endothelial Control of Coronary Blood Flow

Although it is only a thin cell layer lining the coronary arteries, the endothelium is a dynamic, active organ producing and responding to many vasoactive mediators, listed in Table 34–2. NO is the dominant endothelial mediator paralleling ATP from red blood cells and myogenic-mediated vasodilation. The great range and complexity of opposing influences indicate tremendous redundancy with interactions not readily measurable or by completely understood mechanisms. However, the end result of this endothelial complexity, its final common pathway, and the cumulative integrated measure of endothelial function, is simply coronary flow or perfusion, at rest and during stress, acutely or chronically.

Coronary atherosclerosis, diabetes, hypertension, hyperlipidemia, inflammation, age, gender, physical activity, food, stress, adiposity, medications, and other factors may affect coronary blood flow. Endothelium may mediate, to some extent, these effects on coronary blood flow, but their mechanistic roles are poorly understood and cannot be directly manipulated for immediate or short-term diagnostic or therapeutic purposes. On the other hand, healthy living and good risk factor control generally improve endothelial function and coronary flow capacity, with reduced risk of atherosclerosis.

As a component of its complex molecular biology, arteriolar vasodilation with increased coronary blood flow also increases endothelial shear stress that normally triggers epicardial coronary artery vasodilation mediated by NO. However, with endothelial dysfunction, shear-induced epicardial vasodilation is lost or vasoconstriction occurs. Invasive assessment of endothelial dysfunction requires a coronary angiogram at control baseline and after intracoronary acetylcholine. Acetylcholine is an endothelial-dependent arteriolar vasodilator that increases coronary blood and endothelial shear stress, thereby inducing epicardial artery dilation on angiogram. However, with endothelial dysfunction, acetylcholine challenge that increases coronary flow induces epicardial artery vasoconstriction rather than vasodilation on clinical angiograms.^95,96 Endothelial dysfunction is typically very heterogeneous regionally and with time, where different coronary arteries and different parts of coronary arteries have differing degrees of endothelial dysfunction at different times. Coronary atherosclerosis, risk factors, or drugs that block NO inhibit epicardial artery vasodilation, but have little inhibition of ATP-driven coronary arteriolar vasodilation caused by increased metabolic demands.⁹⁷

Noninvasive assessment of endothelial dysfunction utilizes quantitative myocardial perfusion during cold pressor stress by immersing one hand in ice water.^98,99 Normally, cold pressor stress increases coronary blood flow. However, with endothelial dysfunction, coronary cold pressor stress causes epicardial and arteriolar vasoconstriction with reduced coronary blood flow that is associated with long-term development of CAD or adverse coronary events.¹⁰⁰ As another clinical example, with normal endothelial function, eating causes a rise in coronary blood flow. However, with risk factors or CAD, the postprandial lipid surge after a high-fat or high-carbohydrate meal worsens endothelial dysfunction that blocks endothelial-mediated vasodilation or causes vasoconstriction with decreased myocardial perfusion.^101,102 This mechanism partially explains postprandial exercise angina, whereas the same exercise while fasting causes no angina.

Neural Control of Coronary Blood Flow

Both sympathetic and parasympathetic neural networks enervate the coronary arteries, as listed in Table 34–3. The direct neural effect of parasympathetic stimulation is coronary vasodilation that would increase coronary blood flow but is overridden by the fall in systemic blood pressure and HR with reduced metabolic demand resulting in lowered coronary blood flow. Parasympathetic stimuli include carotid sinus massage, intravenous atropine, digoxin, the Bezold-Jarisch reflex from high osmotic intracoronary contrast media, and the parasympathetic reflex from pain. The direct neural effect of parasympathetic blockade is vasoconstriction that would lower coronary blood flow, but is overridden by metabolic demand from the unbalanced sympathetic drive that elevates HR and blood pressure, resulting in increased coronary blood flow.

The direct neural effect of beta-sympathetic blockade causes coronary vasoconstriction augmented by reduced metabolic demand from lowered HR and contractility resulting in decreased coronary blood flow. This neural effect explains why beta blockade may exacerbate coronary spasm and leg claudication. The direct neural effect of beta-sympathetic stimulation is vasodilation augmented by increased metabolic demand caused by beta-sympathetic–driven increased HR and contractility, resulting in increased coronary blood flow.

The direct neural effect of alpha blockade is coronary vasodilation that is overridden by reduced metabolic demand from reduced blood pressure, resulting in decreased coronary blood flow. The direct neural effect of alpha-sympathetic stimulation causes coronary artery vasoconstriction that is overridden by increased metabolic demand from sympathetically driven increased blood pressure, resulting in increased coronary blood flow. Both parasympathetic and sympathetic direct neural effects on coronary blood flow are usually overridden by metabolic demands, but do limit the coronary blood flow response to metabolic demands.

Despite the deeply established relation between coronary blood flow and myocardial ischemia, their use and precise meaning in clinical practice remain surprisingly limited. Use of FFR to guide management has importantly expanded scientific focus from angiographic anatomy to coronary pathophysiology that now continues beyond FFR back to its origins—coronary blood flow. Although quantitative PET perfusion imaging is not commonly available, we use it here to demonstrate the principles and potential of quantitative coronary perfusion in clinical management. Any technology proven to quantify myocardial perfusion or coronary blood flow reliably and accurately will serve as in these examples and detailed in the chapter on PET imaging (Chap. 19). As for complexity or expense, a PET laboratory is simpler and less costly than a catheterization laboratory. Moreover, it requires a different physiologic mindset and corresponding physiologic knowledge and training, which is now lacking in most cardiac facilities and training programs. This review aims to improve this limited knowledge.

This chapter closes with vivid examples in Fig. 34–43²⁵ of current accurate physiologic quantification of coronary blood flow and pathophysiology to guide management of CAD. It is easily understood visually by invasive and noninvasive cardiologists, internists, family practitioners and, most importantly, by patients. The quantitative images return to the basics of coronary blood flow to define myocardial ischemia in universal terms of absolute flow in cc/min/g and CFR as essential vital signs even more basic than blood pressure and HR that depend on coronary blood flow.

As integrated biological, technical, and clinical complexity made simple by relevant knowledge, Fig. 34–43 shows coronary flow capacity maps from 12 separate cases (single views) representing the range of CAD: healthy young volunteers; the healthy middle aged; those only with risk factors; and those with documented CAD with or without segmental stenosis, diffuse disease, coronary events, or revascularization. The blue regions with stress perfusion of 0.9 cc/min/g or less and CFR of 1.7 or less for over 15% of the heart comprise our definition of “ischemia” requiring revascularization-based objective, measurable, universal terms of cc/min/g integrated with clinical circumstances and judgment. Less severe abnormalities comprise regionally reduced coronary flow capacity suitable for medical management that we do not call “ischemia,” depending on clinical circumstances, experience and judgment.

Patients on the left of the blue dashed line are optimally treated medically without need for revascularization to achieve relief of symptoms and reduced risk of myocardial infarction and death. Patients on the right of the blue dashed line are optimally treated with an angiogram and revascularization added to vigorous medical treatment to achieve the same goals. Of course, more randomized trials are needed, but they will likely succeed in providing definitive proof only by patient selection based on quantitative myocardial perfusion or blood flow.

KLG received internal funding and is salaried solely from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis. KLG is the 510(k) applicant for HeartSee, a software package for quantifying absolute flow using cardiac positron emission tomography. All royalties will go to a University of Texas scholarship fund. The University of Texas has has the right to license the HeartSee software in exchange for royalties. However, KLG retains the ability to distribute cost-free versions to selected collaborators for research. Additionally, KLG has financial research support from Volcano Corporation (maker of FFR pressure wires) for the multicenter study DEFINE_FLOW, Clinical Trials number NCT02328820. HG and JN have no financial relationships to disclose.