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Supplemental Digital Content is available in the text. Background: Intracoronary acetylcholine (Ach) provocation testing is the gold standard for assessing coronary endothelial function. However, dosing regimens of Ach are quite varied in the literature, and there are limited data evaluating the optimal dose. We evaluated the dose-response relationship between Ach and minimal lumen diameter (MLD) by sex and studied whether incremental intracoronary Ach doses given during endothelial function testing improve its diagnostic utility. Methods: We evaluated 65 men and 212 women with angina and no obstructive coronary artery disease who underwent endothelial function testing using the highest tolerable dose of intracoronary Ach, up to 200 μg. Epicardial endothelial dysfunction was defined as a decrease in MLD >20% after intracoronary Ach by quantitative coronary angiography. We used a linear mixed effects model to evaluate the dose-response relationship. Deming regression analysis was done to compare the %MLD constriction after incremental doses of intracoronary Ach. Results: The mean age was 53.5 years. Endothelial dysfunction was present in 186 (68.1%). Among men with endothelial dysfunction, there was a significant decrease in MLD/10 µg of Ach at doses above 50 μg and 100 µg, while this decrease in MLD was not observed in women (P <0.001). The %MLD constriction at 20 μg versus 50 μg and 50 μg versus 100 μg were not equivalent while the %MLD constriction at 100 μg versus 200 μg were equivalent. Conclusions: Women and men appear to have different responses to Ach during endothelial function testing. In addition to having a greater response to intracoronary Ach at all doses, men also demonstrate an Ach-MLD dose-response relationship with doses up to 200 μg, while women have minimal change in MLD with doses above 50 µg. An incremental dosing regimen during endothelial function testing appears to improve the diagnostic utility of the test and should be adjusted based on the sex of the patient. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: The prognostic impact of coronary microvascular dysfunction after percutaneous coronary intervention (PCI) remains unclear in patients with stable coronary artery disease. This study sought to investigate the prognostic value of microvascular function measured immediately after PCI in patients with stable coronary artery disease. Methods: We enrolled 572 patients with stable coronary artery disease who underwent PCI and elective measurement of the index of microcirculatory resistance (IMR) immediately after PCI from 8 centers in 4 countries. Impaired microvascular function was defined as IMR≥25 (high IMR). Major adverse cardiac events, including death, myocardial infarction (MI) and target vessel revascularization, were evaluated. Results: During a median follow-up duration of 4.0 years, the cumulative major adverse cardiac events rate was significantly higher in the high IMR group (n=66/148) compared with the low IMR group (n=128/424; hazard ratio [HR], 1.56; 95% CI, 1.16−2.105; P =0.001), primarily due to a higher rate of periprocedural MI (HR, 1.59; 95% CI, 1.11−2.28; P =0.004) but also due to higher rates of mortality (HR, 1.59; 95% CI, 0.76−3.35; P =0.22), spontaneous MI (HR, 2.10; 95% CI, 0.67−6.63; P =0.20) and target vessel revascularization (HR, 1.40; 95% CI, 0.77−2.54; P =0.27). Cumulative risk for death, spontaneous MI, and target vessel revascularization was higher in the high IMR group (HR, 1.55; 95% CI, 0.99−2.43; P =0.056), as was death and spontaneous MI alone (HR, 1.79; 95% CI, 0.96−3.36; P =0.065). On multivariable analysis, high IMR post-PCI was an independent predictor of major adverse cardiac events. Conclusions: IMR measured immediately after PCI predicts adverse events in patients with stable coronary artery disease. [ABSTRACT FROM AUTHOR]

Background: Nonhyperemic pressure ratios (NHPRs) have been proposed as alternatives to fractional flow reserve (FFR) without induction of hyperemia. More recently, imaging based-FFR estimation, especially coronary angiography-derived FFR (Angio-FFR) measurement, is proposed to estimate wire-based FFR. However, little is known about the diagnostic performance of these indices against conventional FFR., Aims: We aimed to assess and compare the diagnostic performance of both NHPRs and coronary Angio-FFR against wire-based conventional FFR., Methods: PubMed and Embase databases were systematically searched for peer-reviewed original articles up to 08/2022. The primary outcomes were the pooled sensitivity and specificity as well as the area under the curve (AUC) of the summary receiver-operating characteristic curve of those indices., Results: A total of 6693 records were identified after a literature search, including 37 reports for NHPRs and 34 for Angio-FFR. Overall, NHPRs have a lower diagnostic performance in estimating wire-based FFR with an AUC of 0.85 (0.81, 0.88) when compared with Angio-FFR of 0.95 (0.93, 0.97). When all four modalities of NHPRs (iFR, Pd/Pa, DPR, RFR) were compared, those had overlapping AUCs without major differences among each other. Similarly, when the two most commonly used Angio-FFR (QFR, FFR angio ) were compared, those had overlapping AUCs without major differences among each other., Conclusion: Angio-FFR may offer a better estimation of wire-based FFR than NHPRs. Our results support a wider use of Angio-FFR in the cardiac catheterization laboratory to streamline our workflow for coronary physiologic assessment., Classifications: FFR,, stable ischemic disease and non-ST elevation acute coronary syndrome., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Previous studies comparing percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) in patients with multivessel coronary disease not involving the left main have shown significantly lower rates of death, myocardial infarction (MI), or stroke after CABG. These studies did not routinely use current-generation drug-eluting stents or fractional flow reserve (FFR) to guide PCI., Methods: FAME 3 (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) is an investigator-initiated, multicenter, international, randomized trial involving patients with 3-vessel coronary artery disease (not involving the left main coronary artery) in 48 centers worldwide. Patients were randomly assigned to receive FFR-guided PCI using zotarolimus drug-eluting stents or CABG. The prespecified key secondary end point of the trial reported here is the 3-year incidence of the composite of death, MI, or stroke., Results: A total of 1500 patients were randomized to FFR-guided PCI or CABG. Follow-up was achieved in >96% of patients in both groups. There was no difference in the incidence of the composite of death, MI, or stroke after FFR-guided PCI compared with CABG (12.0% versus 9.2%; hazard ratio [HR], 1.3 [95% CI, 0.98-1.83]; P =0.07). The rates of death (4.1% versus 3.9%; HR, 1.0 [95% CI, 0.6-1.7]; P =0.88) and stroke (1.6% versus 2.0%; HR, 0.8 [95% CI, 0.4-1.7]; P =0.56) were not different. MI occurred more frequently after PCI (7.0% versus 4.2%; HR, 1.7 [95% CI, 1.1-2.7]; P =0.02)., Conclusions: At 3-year follow-up, there was no difference in the incidence of the composite of death, MI, or stroke after FFR-guided PCI with current-generation drug-eluting stents compared with CABG. There was a higher incidence of MI after PCI compared with CABG, with no difference in death or stroke. These results provide contemporary data to allow improved shared decision-making between physicians and patients with 3-vessel coronary artery disease., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02100722., Competing Interests: Disclosures Dr Pijls receives research funding from Abbott, has consulting relationships with Abbott and Opsens, and has stock or stock options with ASML, General Electric, HeartFlow, Hexacath, and Philips. Dr Mansour has consulting relationships with Abbott Vascular, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, and Servier Affaires, and received a research grant from Opsens Inc and Abbott Vascular. Dr Kala has a consulting relationship with Boston Scientific, Medtronic, and Servier Affaires, and receives honoraria from AstraZeneca and Bayer. Dr Angeras receives research funding from Abbott Vascular and AstraZeneca and has a consulting relationship with Abbott Vascular and Boston Scientific. Dr Miner has a consulting relationship with Abbott, Amgen, Astra Zeneca, Bayer, Boehringer, Novartis, Opsens, Pfizer, and Servier Affaires Medicales. Dr Engstrøm has a consulting relationship with Abbott Vascular, Bayer, and Novo Nordisk. Dr Christiansen has a consulting relationship with Abbott Vascular and has received research grants from Abbott Vascular. Dr Tonino has received research grants from Biosensors and Opsens. Dr Reardon has a consulting relationship with Boston Scientific and W.L. Gore & Associates. Dr Otsuki has received research grants from the Uehara Memorial Foundation, Abbott, Medtronic, Boston Scientific, and Terumo. Dr Kobayashi has a consulting relationship with Abbott Vascular. Dr Hlatky has a consulting relationship with Blue Cross and Blue Shield and research support from HeartFlow. Dr Mahaffey has received research grants or contracts from the American Heart Association, Apple, Inc, Bayer, California Institute Regenerative Medicine, Eidos, Ferring, Gilead, Google (Verily), Idorsia, Johnson & Johnson, Luitpold, PAC-12, Precordior, and Sanifit; has provided consulting or other services for Amgen, Applied Therapeutics, AstraZeneca, Bayer, CSL Behring, Elsevier, FibroGen, Inova, Johnson & Johnson, Lexicon, MyoKardia, Novartis, Novo Nordisk, Otsuka, PhaseBio, Portola, Quidel, Sanofi, and Theravance; and has equity in Precordior. Dr Yeung has a consulting relationship with Medtronic. Dr De Bruyne has an institutional consulting relationship with Boston Scientific, Abbott Vascular, CathWorks, Siemens, GE Healthcare, and Coroventis Research; receives institutional research grants from Abbott Vascular, Coroventis Research, CathWorks, and Boston Scientific; and holds minor equities in Philips, Siemens, GE Healthcare, CathWorks, Edwards Life Sciences, HeartFlow, Opsens, Celyad, Xenter, Medyria, Bayer, and Sanofi. Dr Fearon receives research funding from Abbott, Medtronic, and Boston Scientific and has a consulting relationship with Siemens and CathWorks and stock options with HeartFlow. The other authors report no conflicts of interest.

Traditionally, invasive coronary physiological assessment has focused on the epicardial coronary artery. More recently, appreciation of the importance of the coronary microvasculature in determining patient outcomes has grown. Several invasive modalities for interrogating microvascular function have been proposed. Angiographic techniques have been limited by their qualitative and subjective nature. Doppler wire-derived coronary flow reserve has been applied in research studies, but its clinical role has been limited by its lack of reproducibility, its lack of a clear normal value, and the fact that it is not specific for the microvasculature but interrogates the entire coronary circulation. The index of microcirculatory resistance-a thermodilution-derived measure of the minimum achievable microvascular resistance-is relatively easy to measure, more reproducible, has a clearer normal value, and is independent of epicardial coronary artery stenosis. The index of microcirculatory resistance has been shown to have prognostic value in patients with ST-segment-elevation myocardial infarction and cardiac allograft vasculopathy after heart transplantation. Emerging data demonstrate its role in evaluating patients with chest pain and nonobstructive coronary artery disease. Increasingly, the index of microcirculatory resistance is used as a reference standard for invasively assessing the microvasculature in clinical trials., (© 2017 American Heart Association, Inc.)

Background: Difficulty directly visualizing the coronary microvasculature as opposed to the epicardial coronary artery makes its assessment challenging. The goal of this study is to measure the index of microcirculatory resistance (IMR) in all 3 major coronary vessels to identify the clinical and angiographic predictors of an abnormal IMR., Methods and Results: Ninety-three patients who underwent coronary physiological assessment in all 3 major coronary vessels were prospectively enrolled (59.8±9.4 years with 77.4% men). IMR was corrected using Yong's formula and coronary microvascular dysfunction (CMD) was defined using vessel-specific cutoffs. A global IMR was calculated as the sum of the IMR in all 3 major epicardial vessels. Angiographic epicardial disease severity was assessed with vessel-specific and overall SYNTAX score. Median IMR and fractional flow reserve was 17.2 (Q1-Q3: 13.3-22.9) and 0.92 (0.85-0.97). The majority of patients (59.1%) had no CMD, 23.7% had 1-vessel CMD, 14.0% had 2-vessel CMD, and 3.2% had 3-vessel CMD. CMD was observed at a similar rate in the territories supplied by all 3 major coronary vessels (left anterior descending coronary artery 28.0%, left circumflex artery 19.4%, and right coronary artery 23.7%; P =0.39). Fractional flow reserve had a weak, positive correlation with IMR (ρ=0.16; P <0.01). The SYNTAX score had no significant correlation with IMR, both at a patient level (ρ=-0.002; P =0.99) and a vessel-specific level (ρ=-0.06; P =0.36). By multivariable ordinal logistic regression analysis, no variable was left as an independent predictor of an abnormal IMR., Conclusions: Clinical factors and epicardial coronary disease severity are not predictors of the extent of CMD., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01621438., (© 2017 American Heart Association, Inc.)

Background: Contrast fractional flow reserve (cFFR) is a method for assessing functional significance of coronary stenoses, which is more accurate than resting indices and does not require adenosine. However, contrast media volume and osmolality may affect the degree of hyperemia and therefore diagnostic performance., Methods and Results: cFFR, instantaneous wave-free ratio, distal pressure/aortic pressure at rest, and FFR were measured in 763 patients from 12 centers. We compared the diagnostic performance of cFFR between patients receiving low or iso-osmolality contrast (n=574 versus 189) and low or high contrast volume (n=341 versus 422) using FFR≤0.80 as a reference standard. The sensitivity, specificity, and overall accuracy of cFFR for the low versus iso-osmolality groups were 73%, 93%, and 85% versus 87%, 90%, and 89%, and for the low versus high contrast volume groups were 69%, 99%, and 83% versus 82%, 93%, and 88%. By receiver operating characteristics (ROC) analysis, cFFR provided better diagnostic performance than resting indices regardless of contrast osmolality and volume ( P <0.001 for all groups). There was no significant difference between the area under the curve of cFFR in the low- and iso-osmolality groups (0.938 versus 0.957; P =0.40) and in the low- and high-volume groups (0.939 versus 0.949; P =0.61). Multivariable logistic regression analysis showed that neither contrast osmolality nor volume affected the overall accuracy of cFFR; however, both affected the sensitivity and specificity., Conclusions: The overall accuracy of cFFR is greater than instantaneous wave-free ratio and distal pressure/aortic pressure and not significantly affected by contrast volume and osmolality. However, contrast volume and osmolality do affect the sensitivity and specificity of cFFR., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02184117., (© 2017 American Heart Association, Inc.)

Background: The induction of hyperemia is of importance to precisely assess the functional significance of coronary artery lesions with fractional flow reserve (FFR). Adenosine or ATP alone is used widely in this setting; however, little is known about the additive value of nicorandil, which acts as a nitrate and a K-ATP channel opener, to induce further hyperemia., Patients and Methods: A total of 183 intermediate native coronary artery lesions from 112 patients were prospectively enrolled into this study. FFR was measured using a coronary pressure wire during an intravenous ATP infusion alone (150 mcg/kg/min) (FFRATP) and repeated after an adjunctive intracoronary nicorandil injection (2.0 mg) (FFRATP+Nico)., Results: Physiologic measurements were completed without any severe adverse effects from ATP and nicorandil in all patients. FFRATP and FFRATP+Nico had a strong linear correlation (R=0.79, P<0.001). The FFR value became significantly lower with an adjunctive intracoronary nicorandil injection compared with ATP alone [FFRATP vs. FFRATP+Nico, 0.87 (interquartile range: 0.81-0.92) vs. 0.85 (0.79-0.90), P<0.001]. A total of 18 lesions out of 183 (9.8%) were reclassified after a nicorandil injection (12 from FFR>0.80 to ≤0.80 vs. six from FFR≤0.80 to >0.80, P=0.26). The adjunctive effect of nicorandil was accentuated with each increment of FFRATP strata (per 0.05 increase, P for trend<0.001), but with minimal effect around the borderline FFR zone., Conclusion: An adjunctive intracoronary nicorandil injection is safe, but appears to have little effect in inducing further hyperemia. Therefore, its effect on the clinical scenario is limited.

Background: The aim of this study is to determine the prognostic value of invasively assessing coronary physiology early after heart transplantation., Methods and Results: Seventy-four cardiac transplant recipients had fractional flow reserve, coronary flow reserve, index of microcirculatory resistance (IMR), and intravascular ultrasound performed down the left anterior descending coronary artery soon after (baseline) and 1 year after heart transplantation. The primary end point was the cumulative survival free of death or retransplantation at a mean follow-up of 4.5±3.5 years. The cumulative event-free survival was significantly lower in patients with a fractional flow reserve <0.90 at baseline (42% versus 79%; P=0.01) or an IMR ≥20 measured 1 year after heart transplantation (39% versus 69%; P=0.03). Patients in whom IMR decreased or did not change from baseline to 1 year had higher event-free survival compared with patients with an increase in IMR (66% versus 36%; P=0.03). Fractional flow reserve <0.90 at baseline (hazard ratio, 0.13; 95% confidence interval, 0.02-0.81; P=0.03), IMR ≥20 at 1 year (hazard ratio, 3.93; 95% confidence interval, 1.08-14.27; P=0.04), and rejection during the first year (hazard ratio, 6.00; 95% confidence interval, 1.56-23.09; P=0.009) were independent predictors of death/retransplantation, whereas intravascular ultrasound parameters were not., Conclusions: Invasive measures of coronary physiology (fractional flow reserve and IMR) determined early after heart transplantation are significant predictors of late death or retransplantation., (© 2016 American Heart Association, Inc.)

Background: Local production of C-reactive protein (CRP) in human coronary arterial plaque was reported as a possible marker for local inflammation and vulnerable plaque. Integrated backscatter intravascular ultrasound (IB-IVUS) plaque tissue characterization may detect vulnerable plaque with high local plaque inflammation. Thus, the aim of this study was to clarify the relationship between IB-IVUS-based plaque characteristics and local high-sensitivity C-reactive protein (hs-CRP) production in stable and unstable plaque., Methods and Results: Eighteen patients (nine unstable angina/non-ST-segment elevation myocardial infarction and nine stable angina) were prospectively enrolled. Using the microcatheter, blood samples from the proximal and distal sites of the culprit lesion were obtained to measure local CRP production. Translesional hs-CRP was defined as distal hs-CRP minus proximal hs-CRP of the culprit lesion. Gray-scale and IB-IVUS analyses were carried out at the target lesion. The translesional hs-CRP level tended to be higher in the unstable angina group than in the stable angina group (0.026 ± 0.033 vs. 0.003 ± 0.007 mg/dl, P = 0.050). Gray-scale IVUS-derived indices did not correlate with translesional hs-CRP. However, % lipid pool area by IB-IVUS correlated positively (r = 0.54, P = 0.02) and % fibrosis area correlated negatively with the translesional hs-CRP level (r = -0.52, P = 0.03)., Conclusion: Lipid pool area detected by IB-IVUS is correlated positively with the translesional hs-CRP level.