Adjunctive physiologic and intravascular imaging modalities as described in Chapters 24 and 25 enable operators to 1) direct ischemia-guided revascularization; 2) diagnose microvascular disease, coronary vasospasm, diffuse endothelial dysfunction, myocardial bridging or any combination of these entities; 3) characterize plaque morphology and severity; and 4) optimize acute and long-term percutaneous coronary intervention results. Herein we describe emerging clinical applications of in vivo physiologic and imaging modalities in the settings of stable ischemic heart disease, symptomatic myocardial ischemia without obstructive epicardial atherosclerosis, and acute coronary syndromes.

Physiologic Evaluation of Intermediate Stenoses

As discussed in Chapter 24, fractional flow reserve (FFR) can accurately assess the hemodynamic significance of intermediate coronary lesions (40%-80% diameter stenosis) and guide coronary revascularization in patients with single vessel, multi-vessel, and left main disease. Physiologic assessment can also help simplify and determine the overall interventional approach for complex bifurcation lesions by converting them into a predominantly single lesion. In addition, FFR can be used to assess the need for intervention of jailed side-branches.

Considered the gold standard for invasive physiologic assessment, FFR has been preferred over other coronary indices such as hyperemic stenosis resistance (HSR), coronary flow reserve (CFR) and the instantaneous wave-free ratio (iFR) because it has a normal reference value of 1.00, is reproducible and relatively easy to perform, and has robust literature supporting its use for safely deferring and guiding revascularization.^1-4 While HSR may be even more accurate in predicting the hemodynamic significance of an epicardial lesion, it requires both pressure and flow sensors for measurement and currently does not have substantial data supporting its clinical use.^5,6

In patients with contraindications to adenosine use, non-hyperemic indices such as whole cycle distal pressure to aortic pressure ratio (Pd/Pa) or iFR may be preferable for intermediate lesion assessment. Although predictive of FFR with a diagnostic accuracy of 75% to 85%, Pd/Pa has a narrower gradient window and smaller signal-to-noise ratio, resulting in less robustness for ischemia prediction. For example, a pressure wire drift of ±2 mm Hg resulted in 31% of misclassified study lesions using Pd/Pa, compared to 21% for FFR (P < 0.001).⁷

Another non-hyperemic index, iFR measures the difference between distal and aortic coronary pressure during a specific mid to late diastolic period of the cardiac cycle, known as the wave-free period, when the resting resistance is relatively constant and low. Several studies have suggested that iFR has a diagnostic accuracy of 75% to 85% for identifying a hemodynamically significant FFR.^8-11 The VERIFY study, however, reported a weaker correlation between iFR and FFR and recommended against its use for clinical decision making.¹² Due to the variability of reported correlations between FFR, iFR, and Pd/Pa, the RESOLVE study was undertaken with analysis in a core laboratory to help settle questions surrounding the diagnostic accuracy of iFR and Pd/Pa compared to FFR. In this retrospective multi-center study, an optimal iFR cut point of 0.90 and Pd/Pa cut point of 0.92 demonstrated overall accuracies of 80.4% and 81.5%, respectively, when compared with FFR.¹³ The ADVISE II study, a prospective multicenter trial, also observed similar diagnostic accuracies for an iFR cut point of 0.89 and Pd/Pa cut point of 0.91 (82.5% vs 83.2%).^14,15 The role of iFR was recently clarified following the results of two studies: DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation)¹⁶ and iFR-Swedeheart (Instantaneous Wave-free Ratio versus Fractional Flow Reserve to Guide PCI).¹⁷ Both studies prospectively compared intermediate lesion assessment between FFR- and iFR-guided percutaneous coronary intervention. Two thousand four hundred patients were enrolled in the DEFINE-FLAIR trial and the primary endpoint was the 1-year risk of major adverse cardiac events which were a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization. At 1-year, the primary end point occurred in 6.8% in the iFR group and 7.0% in the FFR group (difference in risk, −0.2 percentage points; 95% confidence interval [CI], −2.3 to 1.8; p<0.001 for noninferiority; hazard ratio, 0.95; 95% CI, 0.68 to 1.33; p=0.78) indicating for the first time that iFR guided revascularization is non-inferior to FFR-guided revascularization. This finding was further illustrated with the iFR-Swedeheart where 2037 patients with stable angina or acute coronary syndrome were randomized to undergo revascularization guided by either iFR or FFR. The primary end point was the rate of a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization within 1-year after the procedure. The primary endpoint in the iFR group occured in 6.7% vs. 6.1% in the FFR group. Following completion of these randomized trials, it became evident that iFR is a promising non-hyperemic index and the technology appears to be quicker and as safe as the established FFR.

Intravascular Imaging for Intermediate Stenoses

The pressure gradient across a stenosis depends on the reference vessel area, stenosis area and length, blood flow velocity and viscosity, entrance effects, and flow separation (Fig. 26-1).³ One might thus expect an imperfect correlation between stenosis geometry and FFR.^18-22 Therefore, it is now accepted that physiologic evaluation is more reliable than anatomic evaluation for assessing intermediate lesion severity. Nevertheless, we discuss below the evidence derived from anatomic lesion assessment.

Non-Left Main Lesions

In a study of 167 patients with intermediate lesions randomized to undergo PCI based on cutoff values of FFR 0.80 or intravascular ultrasound (IVUS)-derived minimum lumen area (MLA) 4.0 mm², neither cohort had increased incidence of major adverse cardiac events, but the IVUS group underwent significantly more revascularization procedures.²⁰ While studies suggest that an IVUS-MLA ≥4.0 mm² can accurately identify non-ischemic lesions for which PCI can be safely deferred, further investigations have supported the importance of considering additional vessel information beyond MLA.^18,21 A meta-analysis of 11 clinical trials demonstrated that the mean MLA of non-left main lesions was 2.6 mm², with a pooled sensitivity of 0.79 and specificity of 0.65. Use of IVUS-MLA was observed to misclassify up to 20% of coronary lesions.²² Given the aforementioned discordances, physiologic evaluation remains superior to anatomic assessment with imaging for intermediate coronary lesions. Anatomic measurements with optical coherence tomography (OCT) imaging are smaller than those with IVUS and correlate better with true anatomic representations from phantom measurements.²³

Bifurcation Lesions

Coronary bifurcations are challenging lesion subsets accounting for 20% of interventional procedures. Pre-intervention intravascular imaging can help select the optimal bifurcation PCI strategy by visualizing the spatial distribution of the mother and daughter vessels as well as identifying carina shifts as a mechanism for side branch compromise.²⁴ Koo et al have demonstrated that jailed side branches with <75% diameter stenosis are almost never hemodynamically significant and therefore often do not need further assessment or treatment.²⁵ Similarly, provisional side branch PCI can usually be deferred if the pre-intervention side branch IVUS-MLA is ≥2.4 mm².²⁶

Left Main Lesions

In addition to difficulty in accurate angiographic assessment as demonstrated by substantial interobserver variability,²⁷ decision making regarding the hemodynamic significance of left main lesions are often more critical. Therefore, adjunctive imaging and physiology modalities have emerged as highly useful tools allowing operators to more confidently and accurately evaluate lesions and direct revascularization. Initial studies suggested that left main MLA <7.5 mm² was hemodynamically significant.²⁸ A subsequent study observed that left main FFR cut point of 0.75 correlated with IVUS-MLA cut point of 5.9 mm².²⁹ More recent data suggest that an IVUS MLA ≤4.5 mm² in the left main artery of Asian patients may correspond to an FFR value of ≤0.80, and that ruptured left main plaque and plaque burden also correlate with FFR.³⁰ An observational outcomes study found that using an IVUS-MLA cut point of 6 mm² to direct or defer revascularization was safe.³¹

Most of the support for the use of IVUS and FFR in left main disease has been derived from small trials and observational studies, so there remain several unanswered questions regarding optimal ischemic cut-off values and long-term safety, efficacy and cost-effectiveness.³² Nevertheless, even for intermediate left main lesions, FFR is considered the gold standard and can be used to guide decision making with regard to the need for revascularization. Importantly, the FFR of left main artery has to be taken in the context of tandem daughter vessel disease (see Chapter 25). Randomized clinical trials directed toward invasive physiologic and anatomic assessment for left main disease are warranted. In the interim, it may be appropriate to start with FFR for angiographically indeterminate left main lesions. If the FFR value is greater than 0.80, then PCI should be deferred, while if it is less than 0.75, the lesion should be revascularized. If the FFR value falls in the grey zone between 0.75 and 0.80, IVUS or other noninvasive functional testing may be helpful (Fig. 26-2).

Patients with anginal syndromes in the absence of significant epicardial disease (<40% diameter stenosis by visual assessment with angiography) likely have myocardial ischemia derived from coronary microvascular disease, vasospasm and/or endothelial dysfunction, or from structural abnormalities such as myocardial bridging, coronary aneurysms, or coronary artery anomalies. Patients with non-obstructive atherosclerosis have longterm outcomes similar to those with obstructive coronary artery disease; anginal symptoms in these patients have been associated with increased mortality, higher frequency of emergency room visits and hospitalizations, increased costs, and worse quality of life when compared to normal subjects.^33,34 Obtaining a definitive diagnosis in such patients can guide targeted intensified lifestyle modification counseling and medical treatment.³⁵ Figure 26-3 outlines a diagnostic approach in the cardiac catheterization laboratory.

Endothelium-independent microvascular assessment is performed with adenosine to induce hyperemia through smooth muscle cell relaxation and microcirculatory vasodilatation. Several indices have been developed to evaluate microvascular function in patients with and without epicardial disease. One established index is CFR, which reflects the combined ability of the epicardial artery and the microcirculation to achieve maximal blood flow in response to stress. In the absence of significant epicardial disease (FFR >0.80), CFR may be used as an index of predominantly microvascular disease, with a CFR <2.0 suggestive of coronary microvascular disease.²

There are other indices that have been developed in recent years to assess microvascular function in patients with or without epicardial lesions. The index of microcirculatory resistance (IMR) can be assessed using a pressure wire and reproducibly measures microvascular function in patients with or without epicardial stenosis; although there are no established cut-off values for IMR, it is emerging as a very practical invasive tool for microvascular testing.³³ Hyperemic microcirculatory resistance (HMR) is also an attractive index that can measure microvascular function independently of epicardial stenosis, but it relies on a combination of pressure and Doppler velocity wire that requires some technical expertise and does not account for collateral reserve.⁵ Microvascular assessments with IMR or HMR are primarily utilized in research cases only.

Endothelial dysfunction is a common cause of microvascular disease and angina in patients with no significant coronary atherosclerotic lesions. Endothelial function testing requires pharmacological interrogation of the endothelium using intracoronary acetylcholine (off-label use) and thus is generally performed in specialized centers or in research protocols.⁵ The healthy endothelium in the presence of acetylcholine induces vasodilatation through stimulation of nitric oxide and cyclic guanosine monophosphate. In patients with endothelial dysfunction, acetylcholine paradoxically fails to cause vasodilatation and may even result in vasoconstriction through interaction on muscarinic receptors of arterial smooth muscle cells.³⁶ Endothelial dysfunction is therefore characterized by the vessel response to intracoronary acetylcholine: epicardial if there is no change or a decrease in diameter as visualized by angiography; and microvascular if there is no change or a decrease in coronary blood flow as determined by angiography in combination with a Doppler velocity wire.^37,38

During acetylcholine administration, vasospasm is identified by reproduction of symptoms or ischemic electrocardiogram changes and classified as epicardial or microvascular depending on the degree of coronary artery diameter reduction in response to acetylcholine. Patients with severe vasospasm may demonstrate complete obliteration of the coronary artery that can be quickly reversed with nitroglycerin.

Myocardial Bridging

While only a minority of myocardial bridges will cause myocardial ischemia, identification of those with hemodynamic relevance is of paramount importance in the diagnosis and management of symptomatic patients.^36,39 Angiography likely underestimates the prevalence of myocardial bridges given its lower detection rate (0.5%-16.0%) compared to autopsy (40%-80%).³⁶ Angiographic manifestations of myocardial bridges include the characteristic step down/step up “U” sign on lateral projections and “coronary milking,” a periodic decrease in luminal dimensions that can be amplified with administration of intracoronary nitroglycerine. Compared to angiography, IVUS is more sensitive in detecting myocardial bridges and can more accurately assess lumen dimensions of the intramyocardial segment.^40-43 IVUS frequently reveals a hypoechogenic “half-moon” image adjacent to the arterial wall within the tunneled segment and has been instrumental in demonstrating the prolongation of luminal obliteration in myocardial bridging during the early- and mid-systolic phase of the cardiac cycle.

Similar to fixed coronary stenoses, the angiographic severity of myocardial bridge does not correlate well with its functional relevance. On the other hand, the physiology of myocardial bridging is significantly different and more complex compared to that of fixed stenoses. During systole, myocardial compression results in highly resistive microcirculation and markedly higher intracoronary pressure, which is observed as a negative pressure gradient across the myocardial bridge where distal pressure is higher than aortic pressure.⁴⁴ Although myocardial bridges exert extravascular coronary compression primarily during systole, this compression also extends into diastole resulting in compromised luminal area and blood flow with positive pressure gradients during the early- and mid-diastolic phases.^36,44,45 Since conventional FFR calculation is based on time-averaged pressures, the negative systolic pressure gradients will invariably affect the detection of the positive diastolic ones if only mean pressures are used.

As a myocardial bridge is a dynamic stenosis that depends on the contractile status of the myocardium and the length of diastole, the hemodynamic consequences of myocardial bridging may only get expressed under stress during increased inotropy and tachycardia, which shortens the diastolic period. Therefore, the hemodynamic significance of a myocardial bridge with FFR should include a dobutamine challenge, which increases coronary blood flow and ionotropy but does not modify epicardial vessel or stenotic dimensions.^44,46 Still, when using conventional FFR, a negative result even after dobutamine challenge does not preclude the possibility of a false negative, and should be interpreted with caution.

In myocardial bridging, this problem can be circumvented by using diastolic FFR with an optimal cutoff value of 0.76.^44,47 The restriction of measurements to diastole not only avoids the influence of negative systolic gradients on overall pressure measurements, but also allows identification and quantification of the effect of the myocardial bridge on the diastolic coronary blood flow.

Intracoronary Doppler has been used to evaluate vessels with myocardial bridging.^41,42,48,49 Flow velocity immediately proximal to the myocardial bridge shows systolic flow reversal, resulting from epicardial blood being squeezed from the compressed coronary segment.⁴⁰ Characteristic abrupt early diastolic flow acceleration has been documented within the myocardial bridge segment in Doppler tracings, reflecting the decreased luminal dimensions caused by the myocardial bridge at that stage of the cardiac cycle.⁴⁹ Additionally, the velocity waveform within myocardial bridge shows a characteristic “fingertip” spike pattern, which denotes a higher flow velocity during early-mid diastole resulting from decreased luminal dimensions during extravascular vessel compression.^36,45 CFR has been observed to be decreased as a consequence of the hemodynamic effect of the myocardial bridge.

Intravascular imaging has been increasingly used in the management of patients presenting with acute coronary syndromes (ACS). Both IVUS and OCT can help the operator identify the location and morphology of the culprit lesion, appropriately select the stent size and optimize stent deployment. Furthermore, innovations in hybrid intravascular imaging and multi-modality fusion may facilitate precise morphologic visualization and phenotypic characterization of culprit lesions. These advances enable decision-making strategies during PCI which potentially reduce rates of late cardiovascular events such as myocardial infarction related to clinical restenosis or stent thrombosis.

Assessing Pathogenesis of the Culprit Lesion

Intravascular imaging has allowed in vivo evaluation of ruptured thin cap fibroatheromas and plaque erosions, which are the most common precursors of coronary occlusions resulting in fatal acute myocardial infarctions.^50,51 For anatomic assessment, intravascular OCT with its superior spatial resolution (10 vs 100 microns for IVUS) allows accurate measurement of the fibrous cap thickness. In contrast, OCT’s lower image penetration depth (1-3 vs 4–8 mm for IVUS) limits its ability to reliably evaluate the entire plaque/media area and vessel remodeling.⁵² Clinical OCT observations demonstrate that 50% of culprit lesions in STEMI patients are due to plaque rupture and 25% to plaque erosions (Fig. 26-4).⁵³

Several clinical applications of intravascular imaging have emerged to better identify high-risk atherosclerotic plaques. Advancements in IVUS technology to improve plaque morphological characterization include virtual histology IVUS, which uses radiofrequency backscatter analysis,⁵⁴ and near-infrared spectroscopy, which estimates the lipid content through a lipid core burden index.⁵⁵ An interesting advancement in OCT technology is the hybridization of OCT with near-infrared autofluorescence, which allows high resolution plaque morphologic visualization with accurate phenotypic characterization.⁵⁶

The quest for modalities with spatial resolution sufficient for cell level visualization has introduced micro-OCT, which uses ultra-broadband light sources and common-path spectral-domain OCT to achieve an axial resolution of less than 1 micron.⁵⁷ Micro-OCT can visualize the cellular and subcellular features of the coronary artery wall associated with atherogenesis and thrombosis as well as responses to interventional therapy, suggesting that it can complement existing diagnostic techniques for investigating progressive atherosclerotic lesions.

Spontaneous Coronary Artery Dissection

Spontaneous coronary artery dissection (SCAD) is an uncommon ACS presentation, with a reported prevalence of approximately 0.3% in patients undergoing angiography for the first time.⁵⁸ Angiography can detect SCAD; however, when angiography is inconclusive, OCT can enhance the diagnostic accuracy by visualizing a double-lumen or an intramural hematoma, identifying the rupture site and measuring the extent of thrombi, true and false lumens.⁵⁹ A potential concern when performing OCT in patients suspected with SCAD is the propagation of the dissection through contrast injection. Nevertheless, an algorithm has been proposed (Fig. 26-5) to utilizing intravascular imaging in identifying and managing SCAD.

Physiologic evaluation can help the operator determine which coronary lesion to intervene upon. As mentioned previously, both FFR and iFR can guide PCI decision making in intermediate stenoses. In critical angiographic stenosis (>90% diameter stenosis by visual assessment), particularly in a symptomatic patient with evidence of myocardial ischemia, further intravascular physiologic testing is not required to decide on hemodynamic lesion severity. On the other hand, both FFR and iFR have been proposed to help perform spot stenting in patients with tandem lesions or diffuse severe disease. Whether physiologically guided spot stenting or anatomically guided “normal to normal” stenting results in superior outcomes has not been prospectively investigated.