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 database25,27,28 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.
Coronary flow reserve (CFR) (red) and stress perfusion in cc/min/g (blue) compared to pressure rate product (PRP) extrapolated from measured values (large “X”) in patients with angina and electrocardiographic changes during dipyridamole stress positron emission tomography (PET) perfusion imaging. Data from 1674 clinical rest stress PET perfusion - PRP measurements. See text for red and blue text phrases. BP, blood pressure (in mm Hg); HR, heart rate (in beats/min); CTO, chronic total occlusion.
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 morphology16,17,18,19 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.