Coronary flow capacity and survival prediction after revascularization: physiological basis and clinical implications.

BACKGROUND AND AIMS: Coronary flow capacity (CFC) is associated with an observed 10-year survival probability for individual patients before and after actual revascularization for comparison to virtual hypothetical ideal complete revascularization. METHODS: Stress myocardial perfusion (mL/min/g) and coronary flow reserve (CFR) per pixel were quantified in 6979 coronary artery disease (CAD) subjects using Rb-82 positron emission tomography (PET) for CFC maps of artery-specific size-severity abnormalities expressed as percent left ventricle with prospective follow-up to define survival probability per-decade as fraction of 1.0. RESULTS: Severely reduced CFC in 6979 subjects predicted low survival probability that improved by 42% after revascularization compared with no revascularization for comparable severity (P = .0015). For 283 pre-and-post-procedure PET pairs, severely reduced regional CFC-associated survival probability improved heterogeneously after revascularization (P < .001), more so after bypass surgery than percutaneous coronary interventions (P < .001) but normalized in only 5.7%; non-severe baseline CFC or survival probability did not improve compared with severe CFC (P = .00001). Observed CFC-associated survival probability after actual revascularization was lower than virtual ideal hypothetical complete post-revascularization survival probability due to residual CAD or failed revascularization (P < .001) unrelated to gender or microvascular dysfunction. Severely reduced CFC in 2552 post-revascularization subjects associated with low survival probability also improved after repeat revascularization compared with no repeat procedures (P = .025). CONCLUSIONS: Severely reduced CFC and associated observed survival probability improved after first and repeat revascularization compared with no revascularization for comparable CFC severity. Non-severe CFC showed no benefit. Discordance between observed actual and virtual hypothetical post-revascularization survival probability revealed residual CAD or failed revascularization.

Quantitative myocardial perfusion in liver transplantation candidates: Poorly metabolized caffeine inhibition of vasodilatory stress.

BACKGROUND: Data on cardiac positron emission tomography (PET) in liver transplantation (LT) candidates are limited with no prior study accounting for poorly metabolized caffeine reducing stress perfusion. METHOD: Consecutive LT candidates (n = 114) undergoing cardiac rest/stress PET were instructed to abstain from caffeine for 2 days extended to 5 and 7 days. Due to persistently high prevalence of measurable blood caffeine after 5-day caffeine abstinence, dipyridamole (n = 41) initially used was changed to dobutamine (n = 73). Associations of absolute flow, coronary flow reserve (CFR), detectable blood caffeine, and Modified End-Stage Liver Disease (MELD) score for liver failure severity were evaluated. Coronary flow data of LT candidates were compared to non-LT control group (n = 102 for dipyridamole, n = 29 for dobutamine). RESULTS: Prevalence of patients with detectable blood caffeine was 63.3%, 36.7% and 33.3% after 2-, 5- and 7-day of caffeine abstinence, respectively. MELD score was associated with detectable caffeine (odd ratio 1.18,P < 0.001). CFR was higher during dipyridamole stress without-caffeine versus with-caffeine (2.22 ± 0.80 vs 1.55 ± 0.37,P = 0.048) but lower than dobutamine stress (2.22 ± 0.80 vs 2.82 ± 1.02,P = 0.026). Mediation analysis suggested that the dominant association between CFR and MELD score in dipyridamole group derived from caffeine-impaired CFR and liver failure/caffeine interaction. CFR in LT candidates was lower than non-LT control population in both dipyridamole and dobutamine group. CONCLUSION: We demonstrate exceptionally high prevalence of detectable blood caffeine in LT candidates undergoing stress PET myocardial perfusion imaging resulting in reduced CFR with dipyridamole compared to dobutamine. The delayed caffeine clearance in LT candidates makes dobutamine a preferred stress agent in this population.

Does financial hardship associate with abnormal quantitative myocardial perfusion and major adverse cardiovascular event?

BACKGROUND: Data on impact of financial hardship on coronary artery disease (CAD) remain incomplete. METHODS: Consecutive subjects referred for clinical rest/stress cardiac positron emission tomography (PET) were enrolled. Financial hardship is defined as patients' inability to pay for their out-of-pocket expense for cardiac PET. Abnormal cardiac PET is defined as at least moderate relative perfusion defects at stress involving > 10% of the left ventricle or global coronary flow reserve ≤ 2.0. Patients were followed for major adverse cardiovascular event (MACE) comprised of all-cause mortality, non-fatal myocardial infarction, and late coronary revascularization. RESULTS: We analyzed a total of 4173 patients with mean age 65.6 ± 11.3 years, 72.2% men, and 93.6% reported as having medical insurance. Of these, 504 (12.1%) patients had financial hardship. On multivariable analysis, financial hardship associated with abnormal cardiac PET (odds ratio 1.377, p = 0.004) and MACE (hazard ratio 1.432, p = 0.010) and its association with MACE was mostly through direct effect with small proportion mediated by abnormal cardiac PET or known CAD. CONCLUSION: Among patients referred for cardiac rest/stress PET, financial hardship independently associates with myocardial perfusion abnormalities and MACE; however, its effect on MACE is largely not mediated by abnormal myocardial perfusion or known CAD suggesting distinct impact of financial hardship beyond traditional risk factors and CAD that deserves attention and intervention to effectively reduced adverse outcomes. Having medical insurance does not consistently protect from financial hardship and a more preventive-oriented restructuring may provide better outcomes at lower cost.

Reliability and Reproducibility of Absolute Myocardial Blood Flow: Does It Depend on the PET/CT Technology, the Vasodilator, and/or the Software?

PURPOSE OF REVIEW: The COURAGE and ISCHEMIA trials showed no reduced mortality after revascularization compared to medical treatment. Is this lack of benefit due to revascularization having no benefit regardless of CAD severity or to suboptimal patient selection due to non-quantitative cardiac imaging? RECENT FINDINGS: Comprehensive, integrated, myocardial perfusion quantified by regional pixel distribution of coronary flow capacity (CFC) is the final common expression of objective CAD severity for which revascularization reduces mortality. Current lack of revascularization benefit derives from narrow thinking focused on measuring one isolated aspect of coronary characteristics, such as angiogram stenosis, its fractional flow reserve (FFR), anatomic FFR simulations, relative stress imaging, absolute stress ml/min/g or coronary flow reserve (CFR) alone, or even more narrowly on global CFR or fixed regions of interest in assumed coronary artery distributions, or in arbitrary 17 segments on bull's-eye displays, rather than regional pixel distribution of perfusion metrics as they actually are in an individual. Comprehensive integration of all quantitative perfusion metrics per regional pixel into coronary flow capacity guides artery-specific interventions for reduced mortality in non-acute CAD but requires addressing the methodologic questions in the title.

Distal Evaluation of Functional performance with Intravascular sensors to assess the Narrowing Effect-combined pressure and Doppler FLOW velocity measurements (DEFINE-FLOW) trial: Rationale and trial design.

BACKGROUND: It remains uncertain if invasive coronary physiology beyond fractional flow reserve (FFR) can refine lesion selection for revascularization or provide additional prognostic value. Coronary flow reserve (CFR) equals the ratio of hyperemic to baseline flow velocity and has a wealth of invasive and noninvasive data supporting its validity. Because of fundamental physiologic relationships, binary classification of FFR and CFR disagrees in approximately 30%-40% of cases. Optimal management of these discordant cases requires further study. AIM: The aim of the study was to determine the prognostic value of combined FFR and CFR measurements to predict the 24-month rate of major adverse cardiac events. Secondary end points include repeatability of FFR and CFR, angina burden, and the percentage of successful FFR/CFR measurements which will not be excluded by the core laboratory. METHODS: This prospective, nonblinded, nonrandomized, and multicenter study enrolled 455 subjects from 12 sites in Europe and Japan. Patients underwent physiologic lesion assessment using the 0.014" Philips Volcano ComboWire XT that provides simultaneous pressure and Doppler velocity sensors. Intermediate coronary lesions received only medical treatment unless both FFR (≤0.8) and CFR (<2.0) were below thresholds. The primary outcome is a 24-month composite of death from any cause, myocardial infarction, and revascularization. CONCLUSION: The DEFINE-FLOW study will determine the prognostic value of invasive CFR assessment when measured simultaneously with FFR, with a special emphasis on discordant classifications. Our hypothesis is that lesions with an intact CFR ≥ 2.0 but reduced FFR ≤ 0.8 will have a 2-year outcome with medical treatment similar to lesions with FFR> 0.80 and CFR ≥ 2.0. Enrollment has been completed, and final follow-up will occur in November 2019.

Phasic pressure measurements for coronary and valvular interventions using fluid-filled catheters: Errors, automated correction, and clinical implications.

OBJECTIVES: We sought to develop an automatic method for correcting common errors in phasic pressure tracings for physiology-guided interventions on coronary and valvular stenosis. BACKGROUND: Effective coronary and valvular interventions rely on accurate hemodynamic assessment. Phasic (subcycle) indexes remain intrinsic to valvular stenosis and are emerging for coronary stenosis. Errors, corrections, and clinical implications of fluid-filled catheter phasic pressure assessments have not been assessed in the current era of ubiquitous, high-fidelity pressure wire sensors. METHODS: We recruited patients undergoing invasive coronary physiology assessment. Phasic aortic pressure signals were recorded simultaneously using a fluid-filled guide catheter and 0.014″ pressure wire before and after standard calibration as well as after pullback. We included additional subjects undergoing hemodynamic assessment before and after transcatheter aortic valve implantation. Using the pressure wire as reference standard, we developed an automatic algorithm to match phasic pressures. RESULTS: Removing pressure offset and temporal shift produced the largest improvements in root mean square (RMS) error between catheter and pressure wire signals. However, further optimization <1 mmHg RMS error was possible by accounting for differential gain and the oscillatory behavior of the fluid-filled guide. The impact of correction was larger for subcycle (like systole or diastole) versus whole-cycle metrics, indicating a key role for valvular stenosis and emerging coronary pressure ratios. CONCLUSIONS: When calibrating phasic aortic pressure signals using a pressure wire, correction requires these parameters: offset, timing, gain, and oscillations (frequency and damping factor). Automatically eliminating common errors may improve some clinical decisions regarding physiology-based intervention.

Coronary Microcirculation in Aortic Stenosis: Pathophysiology, Invasive Assessment, and Future Directions.

With the increasing prevalence of aortic stenosis (AS) due to a growing elderly population, a proper understanding of its physiology is paramount to guide therapy and define severity. A better understanding of the microvasculature in AS could improve clinical care by predicting left ventricular remodeling or anticipate the interplay between epicardial stenosis and myocardial dysfunction. In this review, we combine five decades of literature regarding microvascular, coronary, and aortic valve physiology with emerging insights from newly developed invasive tools for quantifying microcirculatory function. Furthermore, we describe the coupling between microcirculation and epicardial stenosis, which is currently under investigation in several randomized trials enrolling subjects with concomitant AS and coronary disease. To clarify the physiology explained previously, we present two instructive cases with invasive pressure measurements quantifying coexisting valve and coronary stenoses. Finally, we pose open clinical and research questions whose answers would further expand our knowledge of microvascular dysfunction in AS. These trials were registered with NCT03042104, NCT03094143, and NCT02436655.

Pitfalls in quantitative myocardial PET perfusion II: Arterial input function.

RATIONALE: We aimed to define the impact of variable arterial input function on myocardial perfusion severity that may misguide interventional decisions and relates to limited capacity of 3D PET for high-count arterial input function of standard bolus R-82. METHODS: We used GE Discovery-ST 16 slice PET-CT, serial 2D and 3D acquisitions of variable Rb-82 dose in a dynamic circulating arterial function model, static resolution and uniformity phantoms, and in patients with dipyridamole stress to quantify per-pixel rest and stress cc·min-1·g-1, CFR and CFC with (+) and (-) 10% simulated change in arterial input. RESULTS: For intermediate, border zone severity of stress perfusion, CFR and CFC comprising 7% of 3987 cases, simulated arterial input variability of ± 10% may cause over or underestimation of perfusion severity altering interventional decisions. In phantom tests, current 3D PET has capacity for quantifying high activity of arterial input and high-count per-pixel values of perfusion metrics per artery or branches. CONCLUSIONS: Accurate, reproducible arterial input function is essential for at least 7% of patients at thresholds of perfusion severity for optimally guiding interventions and providing high-activity regional per-pixel perfusion metrics by 3D PET for displaying complex quantitative perfusion readily understood ("owned") by interventionalists to guide procedures.

How Do PET Myocardial Blood Flow Reserve and FFR Differ?

PURPOSE OF REVIEW: This review discusses similarities and differences between cardiac positron emission tomography (PET), absolute myocardial blood flow, and flow reserve with invasive fractional flow reserve (FFR). RECENT FINDINGS: Fundamentally, cardiac PET measures absolute myocardial blood flow whereas FFR provides a relative flow reserve. Cardiac PET offers a non-invasive and therefore lower risk alternative, able to image the entire left ventricle regardless of coronary anatomy. While cardiac PET can provide unique information about the subendocardium, FFR pullbacks offer unparalleled spatial resolution. Both diagnostic tests provide a highly repeatable and technically successful index of coronary hemodynamics that accounts for the amount of distal myocardial mass, albeit only indirectly with FFR. The randomized evidence base for FFR and its associated cost effectiveness remains unsurpassed. Cardiac PET and FFR have been intertwined since the very development of FFR over 25 years ago. Recent work has emphasized the ability of both techniques to guide revascularization decisions by high-quality physiology. In the past few years, cardiac PET has expanded its evidence base regarding clinical outcomes, whereas FFR has solidified its position in randomized studies as the invasive reference standard.

Pressure gradient vs. flow relationships to characterize the physiology of a severely stenotic aortic valve before and after transcatheter valve implantation.

Aims: Echocardiography and tomographic imaging have documented dynamic changes in aortic stenosis (AS) geometry and severity during both the cardiac cycle and stress-induced increases in cardiac output. However, corresponding pressure gradient vs. flow relationships have not been described. Methods and results: We recruited 16 routine transcatheter aortic valve implantations (TAVI's) for graded dobutamine infusions both before and after implantation; 0.014″ pressure wires in the aorta and left ventricle (LV) continuously measured the transvalvular pressure gradient (ΔP) while a pulmonary artery catheter regularly assessed cardiac output by thermodilution. Before TAVI, ΔP did not display a consistent relationship with transvalvular flow (Q). Neither linear resistor (median R2 0.16) nor quadratic orifice (median R2 < 0.01) models at rest predicted stress observations; the severely stenotic valve behaved like a combination. The unitless ratio of aortic to left ventricular pressures during systolic ejection under stress conditions correlated best with post-TAVI flow improvement. After TAVI, a highly linear relationship (median R2 0.96) indicated a valid valve resistance. Conclusion: Pressure loss vs. flow curves offer a fundamental fluid dynamic synthesis for describing aortic valve pathophysiology. Severe AS does not consistently behave like an orifice (as suggested by Gorlin) or a resistor, whereas TAVI devices behave like a pure resistor. During peak dobutamine, the ratio of aortic to left ventricular pressures during systolic ejection provides a 'fractional flow reserve' of the aortic valve that closely approximates the complex, changing fluid dynamics. Because resting assessment cannot reliably predict stress haemodynamics, 'valvular fractional flow' warrants study to explain exertional symptoms in patients with only moderate AS at rest.

What can intracoronary pressure measurements tell us about flow reserve? Pressure-Bounded coronary flow reserve and example application to the randomized DEFER trial.

OBJECTIVE: We propose a novel technique called pressure-bounded coronary flow reserve (pb-CFR) and demonstrate its application to the randomized DEFER trial. BACKGROUND: Intracoronary flow reserve assessment remains underutilized relative to pressure measurements partly due to less robust tools. METHODS: While rest and hyperemic intracoronary pressure measurements cannot quantify CFR exactly, they do provide upper and lower bounds. We validated pb-CFR invasively against traditional CFR, then applied it to high fractional flow reserve (FFR ≥ 0.75) lesions in DEFER randomized to revascularization or medical therapy. RESULTS: pb-CFR showed an 84.4% accuracy to predict invasive CFR < 2 or CFR ≥ 2 in 107 lesions. In its proof of concept application to DEFER lesions with FFR ≥ 0.75, the 28 with pb-CFR < 2 compared to 28 with pb-CFR ≥ 2 had a non-significant reduction in freedom from angina (61% vs. 71% at 5 years, P = 0.57) and a non-significantly higher rate of major adverse cardiac events (MACE, 25% vs. 15%, P = 0.34). Lesions with FFR ≥ 0.75 but pb-CFR < 2 showed no difference in freedom from angina (61% vs. 50%, P = 0.54) or MACE (25% vs. 38%, P = 0.27) between the 28 randomized to medical therapy and the 16 randomized to revascularization. CONCLUSIONS: pb-CFR offers a new method for studying FFR/CFR discordances using regular pressure wire measurements. As an example application, DEFER suggested that low pb-CFR with high FFR may be a risk marker for more angina and worse outcomes, but that this risk cannot be modified by revascularization. © 2017 Wiley Periodicals, Inc.

Quantitative Coronary Physiology for Clinical Management: the Imaging Standard.

Pressure derived FFR and coronary flow capacity by PET define a physiologic severity-risk-benefit continuum wherein probability of benefit from revascularization over risk of the procedure and risk of residual global diffuse disease guides personalized, informed, evidenced based, interventional decisions. For the many variations in PET or MRI protocols for quantifying myocardial perfusion to define physiologic severity, the simple standard performance test combining measurement accuracy and clinical coronary pathophysiology to assure correct clinical decisions is the capacity to measure (i) rest perfusion of 0.2 cm(3)/min/gm in transmural scar in at least five patients to test low perfusion accuracy (ii) regional and global CFR of 4.0 or stress perfusion of 2.9 cm(3)/min/gm on two sequential rest-stress PET perfusion studies in the same subject with ±15 % variability for at least 15 young healthy volunteers with no risk factors, no smoking, no obesity, and no measureable blood caffeine levels.

Physiology of endothelin in producing myocardial perfusion heterogeneity: a mechanistic study using darusentan and positron emission tomography.

BACKGROUND: Heterogeneity of resting perfusion may be due in part to up-regulation of coronary vasoconstriction via endothelin (ET) type A receptors, as homogeneity increases during subsequent vasodilatory hyperemia. Therefore, we conducted a mechanistic study using an ET receptor antagonist to determine if it could alter the homogeneity of myocardial perfusion. METHODS: Included subjects demonstrated a low myocardial perfusion homogeneity index (HI) compared to normal volunteers. Four serial cardiac positron emission tomography Rb-82 scans were performed 2 weeks apart. Before the middle two scans, subjects were randomized to receive either darusentan first then placebo or visa versa. Absolute flow and coronary flow reserve were quantified for each study. Rest flow was adjusted for the pressure-rate product (PRP). RESULTS: We screened 37 subjects and randomized 20 who satisfied entry criteria. Rest HI increased significantly while taking darusentan (0.39 ± 0.10 vs 0.33 ± 0.04 on placebo, P = .030, compared to a normal range of 0.52 ± 0.10) without an increase in the PRP (6,859 ± 1,503 vs 6,976 ± 1,092, P = .79), leading to a higher adjusted flow at rest (0.69 ± 0.18 cc/minute/g at 7,000 PRP vs 0.59 ± 0.07 with placebo). CONCLUSIONS: Antagonism of the type A ET receptor increases homogeneity of resting myocardial perfusion. The mechanism appears to be increased absolute rest flow without an increase in either the PRP or myocardial perfusion during hyperemia. Our translational results are consistent with one mechanism for the observed heterogeneity of myocardial perfusion in humans.

Use of a Pressure Wire for Automatically Correcting Artifacts in Phasic Pressure Tracings From a Fluid-Filled Catheter.

BACKGROUND/PURPOSE: Matching phasic pressure tracings between a fluid-filled catheter and high-fidelity pressure wire has received limited attention, although each part contributes half of the information to clinical decisions. We aimed to study the impact of a novel and automated method for improving the phasic calibration of a fluid-filled catheter by accounting for its oscillatory behavior. METHODS/MATERIALS: Retrospective analysis of drift check tracings was performed using our algorithm that corrects for mean difference (offset), temporal delays (timing), differential sensitivity of the manifold transducer and pressure wire sensor (gain), and the oscillatory behavior of the fluid-filled catheter described by its resonant frequency and damping factor (how quickly oscillations disappear after a change in pressure). RESULTS: Among 2886 cases, correcting for oscillations showed a large improvement in 28 % and a medium improvement in 41 % (decrease in root mean square error >0.5 mmHg to <1 or 1-2 mmHg, respectively). 96 % of oscillators were underdamped with median damping factor 0.27 and frequency 10.6 Hz. Fractional flow reserve or baseline Pd/Pa demonstrated no clinically important bias when ignoring oscillations. However, uncorrected subcycle non-hyperemic pressure ratios (NHPR) displayed both bias and scatter. CONCLUSIONS: By automatically accounting for the oscillatory behavior of a fluid-filled catheter system, phasic matching against a high-fidelity pressure wire can be improved compared to standard equalization methods. The majority of tracings contain artifacts, mainly due to underdamped oscillations, and neglecting them leads to biased estimates of equalization parameters. No clinically important bias exists for whole-cycle metrics, in contrast to significant effects on subcycle NHPR.

Subendocardial and Transmural Myocardial Ischemia: Clinical Characteristics, Prevalence, and Outcomes With and Without Revascularization.

BACKGROUND: Subendocardial ischemia is commonly diagnosed but not quantified by imaging. OBJECTIVES: This study sought to define size and severity of subendocardial and transmural stress perfusion deficits, clinical associations, and outcomes. METHODS: Regional rest-stress perfusion in mL/min/g, coronary flow reserve, coronary flow capacity (CFC), relative stress flow, subendocardial stress-to-rest ratio and stress subendocardial-to-subepicardial ratio as percentage of left ventricle were measured by positron emission tomography (PET) with rubidium Rb 82 and dipyridamole stress in serial 6,331 diagnostic PETs with prospective 10-year follow-up for major adverse cardiac events with and without revascularization. RESULTS: Of 6,331 diagnostic PETs, 1,316 (20.7%) had severely reduced CFC with 41.4% having angina or ST-segment depression (STΔ) >1 mm during hyperemic stress, increasing with size. For 5,015 PETs with no severe CFC abnormality, 402 (8%) had angina or STΔ during stress, and 82% had abnormal subendocardial perfusion with 8.7% having angina or STΔ >1 mm during dipyridamole stress. Of 947 cases with stress-induced angina or STΔ >1 mm, 945 (99.8%) had reduced transmural or subendocardial perfusion reflecting sufficient microvascular function to increase coronary blood flow and reduce intracoronary pressure, causing reduced subendocardial perfusion; only 2 (0.2%) had normal subendocardial perfusion, suggesting microvascular disease as the cause of the angina. Over 10-year follow-up (mean 5 years), severely reduced CFC associated with major adverse cardiac events of 44.4% compared to 8.8% for no severe CFC (unadjusted P < 0.00001) and mortality of 15.2% without and 6.9% with revascularization (P < 0.00002) confirmed by multivariable Cox regression modeling. For no severe CFC, mortality was 3% with and without revascularization (P = 0.90). CONCLUSIONS: Reduced subendocardial perfusion on dipyridamole PET without regional stress perfusion defects is common without angina, has low risk of major adverse cardiac events, reflecting asymptomatic nonobstructive diffuse coronary artery disease, or angina without stenosis. Severely reduced CFC causes angina in fewer than one-half of cases but incurs high mortality risk that is significantly reduced after revascularization.