Nils P. Johnson

Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making.

Angiographic severity of coronary artery stenosis has historically been the primary guide to revascularization or medical management of coronary artery disease. However, physiologic severity defined by coronary pressure and/or flow has resurged into clinical prominence as a potential, fundamental change from anatomically to physiologically guided management. This review addresses clinical coronary physiology-pressure and flow-as clinical tools for treating patients. We clarify the basic concepts that hold true for whatever technology measures coronary physiology directly and reliably, here focusing on positron emission tomography and its interplay with intracoronary measurements.

Prognostic Value of Fractional Flow Reserve: Linking Physiologic Severity to Clinical Outcomes

BACKGROUND Fractional flow reserve (FFR) has become an established tool for guiding treatment, but its graded relationship to clinical outcomes as modulated by medical therapy versus revascularization remains unclear. OBJECTIVES The study hypothesized that FFR displays a continuous relationship between its numeric value and prognosis, such that lower FFR values confer a higher risk and therefore receive larger absolute benefits from revascularization. METHODS Meta-analysis of study- and patient-level data investigated prognosis after FFR measurement. An interaction term between FFR and revascularization status allowed for an outcomes-based threshold. RESULTS A total of 9,173 (study-level) and 6,961 (patient-level) lesions were included with a median follow-up of 16 and 14 months, respectively. Clinical events increased as FFR decreased, and revascularization showed larger net benefit for lower baseline FFR values. Outcomes-derived FFR thresholds generally occurred around the range 0.75 to 0.80, although limited due to confounding by indication. FFR measured immediately after stenting also showed an inverse relationship with prognosis (hazard ratio: 0.86, 95% confidence interval: 0.80 to 0.93; p < 0.001). An FFR-assisted strategy led to revascularization roughly half as often as an anatomy-based strategy, but with 20% fewer adverse events and 10% better angina relief. CONCLUSIONS FFR demonstrates a continuous and independent relationship with subsequent outcomes, modulated by medical therapy versus revascularization. Lesions with lower FFR values receive larger absolute benefits from revascularization. Measurement of FFR immediately after stenting also shows an inverse gradient of risk, likely from residual diffuse disease. An FFR-guided revascularization strategy significantly reduces events and increases freedom from angina with fewer procedures than an anatomy-based strategy.

Frequent Diagnostic Errors in Cardiac PET/CT Due to Misregistration of CT Attenuation and Emission PET Images: A Definitive Analysis of Causes, Consequences, and Corrections

Cardiac PET combined with CT is rapidly expanding despite artifactual defects and false-positive results due to misregistration of PET and CT attenuation correction data—the frequency, cause, and correction of which remain undetermined. Methods: Two hundred fifty-nine consecutive patients underwent diagnostic rest–dipyridamole myocardial perfusion PET/CT using 82Rb, a 16-slice PET/CT scanner, helical CT attenuation correction with breathing and also at end-expiratory breath-hold, and averaged cine CT data during breathing. Misregistration on superimposed PET/CT fusion images was objectively measured in millimeters and correlated with associated quantitative size and severity of PET defects. Misregistration artifacts were defined as PET defects with corresponding misregistration on helical CT-PET fusion images that resolved after correct coregistration using a repeat CT scan, cine CT averaged attenuation during normal breathing, or shifted cine CT data that coregistered with PET data. Results: Misregistration of standard helical CT PET images caused artifactual PET defects in 103 of 259 (40%) patients that were moderate to severe in 59 (23%) (P = 0.0000) and quantitatively normalized on cine or shifted cine CT PET (P = 0.0000). Quantitative misregistration was a powerful predictor of artifact size and severity (P = 0.0000), particularly for transaxial misregistration >6 mm occurring in anterior or lateral areas in 76%, in inferior areas in 16%, and at the apex in 8% of 103 artifactual defects. Conclusion: Misregistration of helical CT attenuation and PET emission images causes artifactual defects with false-positive results in 40% of patients that normalize on cine CT PET using averaged CT attenuation data during normal breathing comparable to normal breathing during PET emission scanning and shifting cine CT images to coregister visually with PET.

Is discordance of coronary flow reserve and fractional flow reserve due to methodology or clinically relevant coronary pathophysiology

OBJECTIVES The purpose of this study was to determine whether observed discordance between coronary flow reserve (CFR) and fractional flow reserve (FFR) is due to methodology or reflects basic coronary pathophysiology. BACKGROUND Despite the clinical importance of coronary physiological assessment, relationships between its 2 most common tools, CFR and FFR, remain poorly defined. METHODS The worst CFR and stress relative uptake were recorded from 1,500 sequential cardiac positron emission tomography cases from our center. From the literature, we assembled all combined, invasive CFR-FFR measurements, including a subset before and after angioplasty. Both datasets were compared with a fluid dynamic model of the coronary circulation predicting relationships between CFR and FFR for variable diffuse and focal narrowing. RESULTS A modest but significant linear relationship exists between CFR and FFR both invasively (r = 0.34, p < 0.001) and using positron emission tomography (r = 0.36, p < 0.001). Most clinical patients undergoing CFR or FFR measurements have diffusely reduced CFR consistent with diffuse atherosclerosis or small-vessel disease. The theoretical model predicts linear relationships between CFR and FFR for progressive stenosis with slopes dependent on diffuse narrowing, matching observed data. Reported changes in CFR and FFR with angioplasty agree with model predictions of removing focal stenosis but leaving diffuse disease. Although CFR-FFR concordance is common, discordance is due to dominant or absent diffuse versus focal disease, reflecting basic pathophysiology. CONCLUSIONS CFR is linearly related to FFR for progressive stenosis superimposed on diffuse narrowing. The relative contributions of focal and diffuse disease define the slope and values along the linear CFR and FFR relationship. Discordant CFR and FFR values reflect divergent extremes of focal and diffuse disease, not failure of either tool. With such discordance observed by invasive and noninvasive techniques and also fitting fluid dynamic predictions, it reflects clinically relevant basic coronary pathophysiology, not methodology.

Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting Pd/Pa with fractional flow reserve: the RESOLVE study.

OBJECTIVES This study sought to examine the diagnostic accuracy of the instantaneous wave-free ratio (iFR) and resting distal coronary artery pressure/aortic pressure (Pd/Pa) with respect to hyperemic fractional flow reserve (FFR) in a core laboratory-based multicenter collaborative study. BACKGROUND FFR is an index of the severity of coronary stenosis that has been clinically validated in 3 prospective randomized trials. iFR and Pd/Pa are nonhyperemic pressure-derived indices of the severity of stenosis with discordant reports regarding their accuracy with respect to FFR. METHODS iFR, resting Pd/Pa, and FFR were measured in 1,768 patients from 15 clinical sites. An independent physiology core laboratory performed blinded off-line analysis of all raw data. The primary objectives were to determine specific iFR and Pd/Pa thresholds with ≥90% accuracy in predicting ischemic versus nonischemic FFR (on the basis of an FFR cut point of 0.80) and the proportion of patients falling beyond those thresholds. RESULTS Of 1,974 submitted lesions, 381 (19.3%) were excluded because of suboptimal acquisition, leaving 1,593 for final analysis. On receiver-operating characteristic analysis, the optimal iFR cut point for FFR ≤0.80 was 0.90 (C statistic: 0.81 [95% confidence interval: 0.79 to 0.83]; overall accuracy: 80.4%) and for Pd/Pa was 0.92 (C statistic: 0.82 [95% confidence interval: 0.80 to 0.84]; overall accuracy: 81.5%), with no significant difference between these resting measures. iFR and Pd/Pa had ≥90% accuracy to predict a positive or negative FFR in 64.9% (62.6% to 67.3%) and 48.3% (45.6% to 50.5%) of lesions, respectively. CONCLUSIONS This comprehensive core laboratory analysis comparing iFR and Pd/Pa with FFR demonstrated an overall accuracy of ~80% for both nonhyperemic indices, which can be improved to ≥90% in a subset of lesions. Clinical outcome studies are required to determine whether the use of iFR or Pd/Pa might obviate the need for hyperemia in selected patients.

Integrating noninvasive absolute flow, coronary flow reserve, and ischemic thresholds into a comprehensive map of physiological severity

Noninvasive, absolute myocardial perfusion and coronary flow reserve (CFR) can be imaged by many techniques. However, such data must be interpreted for clinical application regardless of its source. Currently, no guide exists for physiological integration. Therefore, we propose 2-dimensional scatter plots of stress flow and CFR with superimposed thresholds for normal flow, reduced flow without ischemia, definite ischemia, and transmural infarction to allow for automatic and objective classification. Application of this schema to 1,500 studies demonstrates that flow capacity relates inversely to risk factors and atherosclerotic burden. Interpreting stress flow to make clinical decisions requires rest flow or CFR for broad application to all patients. Although relative uptake images alone are adequate for some patients, it can either under- or over-estimate flow capacity in many persons. Our standardized framework could prompt future studies leading to a trial of revascularization guided by absolute flow measurements.

Physiological basis for angina and ST-segment change PET-verified thresholds of quantitative stress myocardial perfusion and coronary flow reserve.

OBJECTIVES This study aimed to determine the quantitative low-flow threshold for stress-induced perfusion defects with severe angina and/or significant ST-segment depression during dipyridamole hyperemia. BACKGROUND Vasodilator stress reveals differences in regional perfusion without ischemia in most patients. However, in patients with a perfusion defect, angina, and/or significant ST-segment depression during dipyridamole stress, quantitative absolute myocardial perfusion and coronary flow reserve (CFR) at the exact moment of definite ischemia have not been established. Defining these low-flow thresholds of angina or ST-segment changes may offer insight into physiological disease severity in patients with atherosclerosis. METHODS Patients underwent rest-dipyridamole stress positron emission tomography (PET) with absolute flow quantification in ml/min/g. Definite ischemia was defined as a new or worse perfusion defect during dipyridamole stress with significant ST-segment depression and/or severe angina requiring pharmacological treatment. Indeterminate clinical features required only 1 of these 3 abnormalities. The comparison group included patients without prior myocardial infarction, or angina or electrocardiographic changes after dipyridamole. RESULTS In 1,674 sequential PET studies, we identified 194 (12%) with definite ischemia, 840 (50%) studies with no ischemia, and 301 (18%) that were clinically indeterminate. A vasodilator stress perfusion cutoff of 0.91 ml/min/g optimally separated definite from no ischemia with an area under the receiver-operator characteristic curve (AUC) of 0.98 and a CFR cutoff of 1.74 with an AUC = 0.91, reflecting excellent discrimination at the exact moment of definite ischemia. CONCLUSIONS Thresholds of low myocardial vasodilator stress perfusion in ml/min/g and CFR sharply separate patients with angina or ST-segment change from those without these manifestations of ischemia during dipyridamole stress with excellent discrimination. Stress flow below 0.91 ml/min/g in dipyridamole-induced PET perfusion defects causes significant ST-segment depression and/or severe angina. However, when the worst vasodilator stress flow exceeds 1.12 ml/min/g, these manifestations of ischemia occur rarely.

Continuum of Vasodilator Stress From Rest to Contrast Medium to Adenosine Hyperemia for Fractional Flow Reserve Assessment

OBJECTIVES This study compared the diagnostic performance with adenosine-derived fractional flow reserve (FFR) ≤0.8 of contrast-based FFR (cFFR), resting distal pressure (Pd)/aortic pressure (Pa), and the instantaneous wave-free ratio (iFR). BACKGROUND FFR objectively identifies lesions that benefit from medical therapy versus revascularization. However, FFR requires maximal vasodilation, usually achieved with adenosine. Radiographic contrast injection causes submaximal coronary hyperemia. Therefore, intracoronary contrast could provide an easy and inexpensive tool for predicting FFR. METHODS We recruited patients undergoing routine FFR assessment and made paired, repeated measurements of all physiology metrics (Pd/Pa, iFR, cFFR, and FFR). Contrast medium and dose were per local practice, as was the dose of intracoronary adenosine. Operators were encouraged to perform both intracoronary and intravenous adenosine assessments and a final drift check to assess wire calibration. A central core lab analyzed blinded pressure tracings in a standardized fashion. RESULTS A total of 763 subjects were enrolled from 12 international centers. Contrast volume was 8 ± 2 ml per measurement, and 8 different contrast media were used. Repeated measurements of each metric showed a bias <0.005, but a lower SD (less variability) for cFFR than resting indexes. Although Pd/Pa and iFR demonstrated equivalent performance against FFR ≤0.8 (78.5% vs. 79.9% accuracy; p = 0.78; area under the receiver-operating characteristic curve: 0.875 vs. 0.881; p = 0.35), cFFR improved both metrics (85.8% accuracy and 0.930 area; p < 0.001 for each) with an optimal binary threshold of 0.83. A hybrid decision-making strategy using cFFR required adenosine less often than when based on either Pd/Pa or iFR. CONCLUSIONS cFFR provides diagnostic performance superior to that of Pd/Pa or iFR for predicting FFR. For clinical scenarios or health care systems in which adenosine is contraindicated or prohibitively expensive, cFFR offers a universal technique to simplify invasive coronary physiological assessments. Yet FFR remains the reference standard for diagnostic certainty as even cFFR reached only ∼85% agreement.

Does the instantaneous wave-free ratio approximate the fractional flow reserve?

OBJECTIVES This study sought to examine the clinical performance of and theoretical basis for the instantaneous wave-free ratio (iFR) approximation to the fractional flow reserve (FFR). BACKGROUND Recent work has proposed iFR as a vasodilation-free alternative to FFR for making mechanical revascularization decisions. Its fundamental basis is the assumption that diastolic resting myocardial resistance equals mean hyperemic resistance. METHODS Pressure-only and combined pressure-flow clinical data from several centers were studied both empirically and by using pressure-flow physiology. A Monte Carlo simulation was performed by repeatedly selecting random parameters as if drawing from a cohort of hypothetical patients, using the reported ranges of these physiologic variables. RESULTS We aggregated observations of 1,129 patients, including 120 with combined pressure-flow data. Separately, we performed 1,000 Monte Carlo simulations. Clinical data showed that iFR was +0.09 higher than FFR on average, with ±0.17 limits of agreement. Diastolic resting resistance was 2.5 ± 1.0 times higher than mean hyperemic resistance in patients. Without invoking wave mechanics, classic pressure-flow physiology explained clinical observations well, with a coefficient of determination of >0.9. Nearly identical scatter of iFR versus FFR was seen between simulation and patient observations, thereby supporting our model. CONCLUSIONS iFR provides both a biased estimate of FFR, on average, and an uncertain estimate of FFR in individual cases. Diastolic resting myocardial resistance does not equal mean hyperemic resistance, thereby contravening the most basic condition on which iFR depends. Fundamental relationships of coronary pressure and flow explain the iFR approximation without invoking wave mechanics.

Quantification of Absolute Myocardial Blood Flow by Magnetic Resonance Perfusion Imaging

By serially imaging the myocardium during the initial transit of gadolinium contrast, magnetic resonance perfusion imaging can accurately assess relative reductions in regional myocardial blood flow and identify hemodynamically significant coronary artery disease. Models can be used to quantify myocardial blood flow (in milliliters/minute/gram) on the basis of dynamic signal changes within the myocardium and left ventricular cavity. Although the mathematical modeling involved in this type of analysis adds complexity, the benefits of absolute blood flow quantification might improve clinical diagnosis and have important implications for cardiovascular research.