The role of coronary physiology in contemporary percutaneous coronary interventions.

: Invasive assessment of coronary physiology has radically changed the paradigm of myocardial revascularization in patients with coronary artery disease. Despite the prognostic improvement associated with ischemia-driven revascularization strategy, functional assessment of angiographic intermediate epicardial stenosis remains largely underused in clinical practice. Multiple tools have been developed or are under development in order to reduce the invasiveness, cost, and extra procedural time associated with the invasive assessment of coronary physiology. Besides epicardial stenosis, a growing body of evidence highlights the role of coronary microcirculation in regulating coronary flow with consequent pathophysiological and clinical and prognostic implications. Adequate assessment of coronary microcirculation function and integrity has then become another component of the decision-making algorithm for optimal diagnosis and treatment of coronary syndromes. This review aims at providing a comprehensive description of tools and techniques currently available in the catheterization laboratory to obtain a thorough and complete functional assessment of the entire coronary tree (both for the epicardial and microvascular compartments).

Effect of Patient-Specific Coronary Flow Reserve Values on the Accuracy of MRI-Based Virtual Fractional Flow Reserve

The purpose of this study is to investigate the effect of varying coronary flow reserve (CFR) values on the calculation of computationally-derived fractional flow reserve (FFR). CFR reflects both vessel resistance due to an epicardial stenosis, and resistance in the distal microvascular tissue. Patients may have a wide range of CFR related to the tissue substrate that is independent of epicardial stenosis levels. Most computationally based virtual FFR values such as FFRCT do not measure patient specific CFR values but use a population-average value to create hyperemic flow conditions. In this study, a coronary arterial computational geometry was constructed using magnetic resonance angiography (MRA) data acquired in a patient with moderate CAD. Coronary flow waveforms under rest and stress conditions were acquired in 13 patients with phase-contrast magnetic resonance (PCMR) to calculate CFR, and these flow waveforms and CFR values were applied as inlet flow boundary conditions to determine FFR based on computational fluid dynamics (CFD) simulations. The stress flow waveform gave a measure of the functional significance of the vessel when evaluated with the physiologically-accurate behavior with the patient-specific CFR. The resting flow waveform was then scaled by a series of CFR values determined in the 13 patients to simulate how hyperemic flow and CFR affects FFR values. We found that FFR values calculated using non–patient-specific CFR values did not accurately predict those calculated with the true hyperemic flow waveform. This indicates that both patient-specific anatomic and flow information are required to accurately non-invasively assess the functional significance of coronary lesions.

Coronary Microvascular Adaptations Distal to Epicardial Artery Stenosis

Until recently, epicardial coronary stenosis has been considered the primary outcome of coronary heart disease and clinical interventions have been dedicated primarily to identification and removal of flow-limiting stenoses. However, a growing body of literature indicates that both epicardial stenosis and microvascular dysfunction contribute to damaging myocardial ischemia. In this review, we discuss the co-existence of macro- and microvascular disease, and how the structure and function of the distal microcirculation is impacted by the hemodynamic consequences of an epicardial, flow-limiting stenosis. Mechanisms of endothelial dysfunction as well as alterations of smooth muscle function in the coronary microcirculation distal to stenosis are discussed. Risk factors including diabetes, metabolic syndrome, and aging exacerbate microvascular dysfunction in the myocardium distal to a stenosis, and our current understanding of the role of these factors in limiting collateralization and angiogenesis of the ischemic myocardium is presented. Importantly, exercise training has been shown to promote collateral growth and improve microvascular function distal to stenosis; thus, the current literature reporting the mechanisms that underlie the beneficial effects of exercise training in the microcirculation distal to epicardial stenosis is reviewed. We also discuss recent studies of therapeutic interventions designed to improve microvascular function and stimulate angiogenesis in clinically relevant animal models of epicardial stenosis and microvascular disease. Finally, microvascular adaptation to removal of epicardial stenosis is considered.

Diagnostic accuracy of Instantaneous Wave-Free Ratio (iFR) for the assessment of myocardial ischaemia: a comparison with non-invasive stress imaging

Background Instantaneous Wave-Free Ratio (iFR) allows for the assessment of the haemodynamic effects of epicardial coronary stenoses without the need for hyperaemia; iFR is currently recommended as a means to evaluate myocardial ischaemia. Purpose To assess the diagnostic accuracy of iFR with respect to the identification of coronary epicardial stenoses causing ischemia. Therefore, we combined anatomical (% stenosis at invasive coronary angiography, ICA) and functional (non-invasive imaging stress test, NIST) information to obtain a “gold standard” for the identification of stenoses causing ischaemia. Methods We enrolled 71 patients (52 male, 19 female; age mean 68.4±8.1 years) with chronic coronary syndrome or low-risk acute coronary syndrome without ST segment elevation who had at least a NIST and who had at least one vessel with a 50%-85% stenosis at ICA. iFR was measured in all coronary arteries with stenosis >50% and categorised according to the 0.89 threshold for ischaemia. Results iFR was assessed in 122 vessels. In a per-vessel analysis, in 56.7% ischaemia was present both at iFR and NIST, in 21.3% ischaemia was absent in both, while in 23.0% ischaemia was found at NIST but not confirmed by iFR. The overall accuracy of iFR with respect to NIST was 90.1%. However, when considering as the “gold standard” for coronary disease causing ischaemia the contemporary presence of an epicardial stenosis >70% at ICA and a positive NIST, the diagnostic accuracy of iFR greatly improved. The sensibility, specificity, PPV, NPV and accuracy were 96.5%, 75.0%, 73.3%, 96.7% and 84.4%, respectively. In case of discordance between NIST and iFR, revascularization was based on iFR. At a mean follow-up of 23±18 months, the composite endpoint of MACE (major adverse cardiac events, defined as the composite of all-cause death, nonfatal MI and unplanned coronary revascularization) occurred in 16.4%, while death/MI occurred in 11.9%. Stratification according to the per-patient concordance between iFR and NIST showed no significant differences in rates of MACE (p=0.50) and death/MI (p=0.20). Stratification based on iFR showed a higher death/MI rate in iFR-positive patients (11.9% vs. 0%, p=0.047) and a trend to higher MACE rate (11.9% vs. 4.47% p=0.14), Conclusions The diagnostic accuracy of iFR is low when compared with NIST as the reference for myocardial ischaemia, but it is very high when compared with the combined presence of epicardial stenosis and positive NIST. Therefore, iFR can accurately guide the decision to treat or defer revascularization of intermediate coronary stenoses, being most useful in patients with multivessel CAD and when non-invasive functional data are lacking or discordant with anatomy. Funding Acknowledgement Type of funding source: None

Diagnostic value of myocardial perfusion CT to detect coexisting microvascular dysfunction in patients with obstructive epicardial coronary disease

Background The usefulness of computed tomography myocardial perfusion (CTP) to assess hemodynamically significant coronary artery lesions has been previously reported. However, the diagnostic value of quantitative evaluation of regional absolute coronary flow by CTP to detect microvascular dysfunction remains unknown. Purpose The aim of study is to assess the diagnostic value of preprocedural CTP to detect coexisting microvascular dysfunction with functionally significant epicardial stenosis in patients with chronic coronary syndromes. Methods and results Thirty-three chronic coronary syndrome patients with de novo single functionally significant stenosis (Fractional flow reserve [FFR]<0.80) who underwent noncomplicated PCI were investigated. In CTP analysis, regional myocardial blood flow (MBF) at rest (rest-MBF) and hyperemia (hyperemic-MBF) were evaluated semi-automatically. Clinical characteristics, pressure-temperature sensor-chipped wire-based information and CTP findings were compared between groups with and without microvascular dysfunction defined by the index of microcirculatory resistance (IMR) (IMR≥25, n=17, IMR<25, n=16, respectively). The determinants of coexistence of microvascular dysfunction and functional epicardial stenosis were determined. In invasive wire-based analysis, FFR, coronary flow reserve (CFRwire) and IMR were 0.68 (0.57–0.72), 1.61 (1.00–1.98), and 26.7 (19.3–39.4) respectively. In CTP analysis, rest and hyperemic-MBF and CFR derived from CTP (CFRCTP; calculated as hyperemic-MBF/rest-MBF) were 2.00 (1.31–2.35) ml/min/g, 4.03 (2.11–5.44) ml/min/g, and 2.09 (1.49–2.09) respectively. In the lesions with IMR>25, hyperemic-MBF was significantly lower than that in IMR<25 (3.42 [1.89–4.34] vs 4.50 [3.44–5.99], p=0.031), although there was no significant difference in regional rest-MBF and CFRCTP (1.75 [1.31–2.24] vs 2.05 [1.35–2.46], p=0.439, and 1.83 [1.21–2.11] vs 2.61 [1.91–2.91], p=0.101 respectively). Receiver operating characteristic curve analysis of hyperemic-MBF detecting IMR>25 showed area under the curve of 0.72 (0.54–0.90), sensitivity of 47% and specificity of 94%. Conclusion Quantitative assessment of absolute coronary flow by CTP may help detect coexisting microvascular dysfunction in patients with significant epicardial stenotic lesions. Funding Acknowledgement Type of funding source: None

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.

P2703Impact of subtended myocardial mass on the assessment of functional ischemia as evaluated by FFR and QFR

Background The fractional flow reserve (FFR) becomes a standard practice for revascularization decision-making in evaluating the functional significance of angiographically intermediate epicardial coronary stenosis. The quantitative flow ratio (QFR) is a novel method for rapid computational estimation of FFR without pressure wire and hyperemic induction. FFR has been reported to be associated with not only epicardial stenosis but also subtended myocardial mass (Vsub). In contrast, the relationship between QFR and Vsub has not been clarified. Purpose We sought to examine if subtended myocardial mass (Vsub) assessed by coronary computed tomography showed a significant relationship with QFR in comparison with FFR. Methods and results We performed a post-hoc analysis of 152 territories (LAD 116, RCA 25 and LCX 11 lesions) with angiographically intermediate-to-severe stenosis in 152 patients who underwent FFR assessment. The median FFR and QFR values were 0.76 (0.64–0.84) and 0.76 (0.72–0.83), respectively. The median diameter stenosis (%DS) and minimum lumen diameter (MLD) were 54.5 (43.9–64.2) and 1.2 (0.9–1.6), respectively. In total, 123 (80.9%) and 29 (19.1%) lesions showed concordant and discordant FFR and QFR functional classifications, respectively. The ability of Vsub/MLD2 to discriminate lesions with FFR≤0.80 and QFR≤0.80 was assessed compared with QCA data. FFR values were associated with Vsub (R=0.37, P<0.001). In contrast, a trend albeit no significant linear relationshipwas detected between QFR and Vsub (R=0.15, P=0.060). The area under the curve (AUC) of Vsub/MLD2 predicting FFR≤0.80 (0.88: 95% confidence interval [CI], 0.83–0.94)was significantly better than that of MLD (0.80: 95% [CI], 0.72–0.88) (P<0.001). On the other hand, the AUC of Vsub/MLD2 predicting QFR≤0.80 (0.82: 95% [CI], 0.75–0.90) was similar to that of MLD (0.80: 95% [CI], 0.72–0.87) (P=0.276). Multivariate analysis showed that the value of Vsub/MLD2 was an independent predictor of FFR≤0.80 (odds ratio [OR]: 1.09, 95% [CI]: 1.03–1.15, P=0.002), whereas it was not an independent predictor of QFR≤0.80. Conclusions Subtended cardiac mass volume derived from CT segmentation improved the diagnostic performance of angiography-derived parameters to identify ischemia-producing lesions when FFR used as a reference standard, whereas QFR showed non-significant relationship with subtended cardiac mass.

Microvascular (dys)Function in Stable Coronary Artery Disease: Cross Talk with Epicardial Segments

Myocardial ischemia is the consequence of an unbalance between coronary flow that can be achieved and myocardial metabolic needs. Pathological state of both epicardial and intramyocardial vessels may be responsible for inducing ischemia. However, revascularization decision should be based on the severity of each epicardial lesion that is evaluated. There are different diagnostic tools that may help for the evaluation of each compartment which is based on the measurement of coronary hemodynamics. Pressure-derived indices are recommended by current guidelines for evaluation of epicardial stenosis significance. We assess the complex interaction between hemodynamic parameters in order to understand how different parameters are influenced in the settings of microvascular dysfunction.

CT Myocardial Perfusion Imaging: A New Frontier in Cardiac Imaging

The past two decades have witnessed rapid and remarkable technical improvement of multidetector computed tomography (CT) in both image quality and diagnostic accuracy. These improvements include higher temporal resolution, high-definition and wider detectors, the introduction of dual-source and dual-energy scanners, and advanced postprocessing. Current new generation multidetector row (≥64 slices) CT systems allow an accurate and reliable assessment of both coronary epicardial stenosis and myocardial CT perfusion (CTP) imaging at rest and during pharmacologic stress in the same examination. This novel application makes CT the unique noninvasive “one-stop-shop” method for a comprehensive assessment of both anatomical coronary atherosclerosis and its physiological consequences. Myocardial CTP imaging can be performed with different approaches such as static arterial first-pass imaging, and dynamic CTP imaging, with their own advantages and disadvantages. Static CTP can be performed using single-energy or dual-energy CT, employing qualitative or semiquantitative analysis. In addition, dynamic CTP can obtain quantitative data of myocardial blood flow and coronary flow reserve. The purpose of this review was to summarize all available evidence about the emerging role of myocardial CTP to identify ischemia-associated lesions, focusing on technical considerations, clinical applications, strengths, limitations, and the more promising future fields of interest in the broad spectra of ischemic heart disease.