The dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current ca...Show moreThe dysregulated expression of immune checkpoint molecules enables cancer cells to evade immune destruction. While blockade of inhibitory immune checkpoints like PD-L1 forms the basis of current cancer immunotherapies, a deficiency in costimulatory signals can render these therapies futile. CD58, a costimulatory ligand, plays a crucial role in antitumor immune responses, but the mechanisms controlling its expression remain unclear. Using two systematic approaches, we reveal that CMTM6 positively regulates CD58 expression. Notably, CMTM6 interacts with both CD58 and PD-L1, maintaining the expression of these two immune checkpoint ligands with opposing functions. Functionally, the presence of CMTM6 and CD58 on tumor cells significantly affects T cell-tumor interactions and response to PD-L1−PD-1 blockade. Collectively, these findings provide fundamental insights into CD58 regulation, uncover a shared regulator of stimulatory and inhibitory immune checkpoints, and highlight the importance of tumor-intrinsic CMTM6 and CD58 expression in antitumor immune responses. Show less
The coronary vascular volume to left ventricular mass (V/M) ratio assessed by coronary computed tomography angiography (CCTA) is a promising new parameter to investigate the relation of coronary... Show moreThe coronary vascular volume to left ventricular mass (V/M) ratio assessed by coronary computed tomography angiography (CCTA) is a promising new parameter to investigate the relation of coronary vasculature to the myocardium supplied. It is hypothesized that hypertension decreases the ratio between coronary volume and myocardial mass by way of myocardial hypertrophy, which could explain the detected abnormal myocardial perfu-sion reserve reported in patients with hypertension. Individuals enrolled in the multicen-ter ADVANCE (Assessing Diagnostic Value of Noninvasive FFRCT in Coronary Care) registry who underwent clinically indicated CCTA for analysis of suspected coronary artery disease with known hypertension status were included in current analysis. The V/ M ratio was calculated from CCTA by segmenting the coronary artery luminal volume and left ventricular myocardial mass. In total, 2,378 subjects were included in this study, of whom 1,346 (56%) had hypertension. Left ventricular myocardial mass and coronary volume were higher in subjects with hypertension than normotensive patients (122.7 & PLUSMN; 32.8 g vs 120.0 & PLUSMN; 30.5 g, p = 0.039, and 3,105.0 & PLUSMN; 992.0 mm3 vs 2,965.6 & PLUSMN; 943.7 mm3, p <0.001, respectively). Subsequently, the V/M ratio was higher in patients with hyperten-sion than those without (26.0 & PLUSMN; 7.6 mm3/g vs 25.3 & PLUSMN; 7.3 mm3/g, p = 0.024). After correcting for potential confounding factors, the coronary volume and ventricular mass remained higher in patients with hypertension (least square) mean difference estimate: 196.3 (95% confidence intervals [CI] 119.9 to 272.7) mm3, p <0.001, and 5.60 (95% CI 3.42 to 7.78) g, p <0.001, respectively), but the V/M ratio was not significantly different (least square mean difference estimate: 0.48 (95% CI -0.12 to 1.08) mm3/g, p = 0.116). In conclusion, our findings do not support the hypothesis that the abnormal perfusion reserve would be caused by reduced V/M ratio in patients with hypertension. & COPY; 2023 The Author(s). Pub-lished by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/) (Am J Cardiol 2023;199:100-109) Show less
Background: Diabetes mellitus is a major risk factor for coronary artery disease (CAD) and may provoke structural and functional changes in coronary vasculature. The coronary volume to left... Show moreBackground: Diabetes mellitus is a major risk factor for coronary artery disease (CAD) and may provoke structural and functional changes in coronary vasculature. The coronary volume to left ventricular mass (V/M) ratio is a new anatomical parameter capable of revealing a potential physiological imbalance between coronary vasculature and myocardial mass. The aim of this study was to examine the V/M derived from coronary computed tomography angiography (CCTA) in patients with diabetes. Methods: Patients with clinically suspected CAD enrolled in the ADVANCE (Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care) registry and known diabetic status were included. Coronary artery volume and left ventricular myocardial mass were analyzed from CCTA and the V/M ratio was calculated and compared between patients with and without diabetes. Results: Of the 3053 patients (age 66 +/- 10 years; 66% male) with known diabetic status, diabetes was present in 21.9%. Coronary volume was lower in patients with diabetes compared to those without diabetes (2850 +/- 940 mm(3) vs. 3040 +/- 970 mm(3), p < 0.0001), whereas the myocardial mass was comparable between the 2 groups (122 +/- 33 g vs. 122 +/- 32 g, p = 0.70). The V/M ratio was significantly lower in patients with diabetes (23.9 +/- 6.8 mm(3)/g vs. 25.7 +/- 7.5 mm(3)/g, p < 0.0001). Among subjects with obstructive CAD (n = 2191, 24.0% diabetics) and non-obstructive CAD (16.7% diabetics), the V/M ratio was significantly lower in patients with diabetes compared to those without (23.4 +/- 6.7 mm(3)/g vs. 25.0 +/- 7.3 mm(3)/g, p < 0.0001 and 25.6 +/- 6.9 mm(3)/g vs. 27.3 +/- 7.6 mm(3)/g, respectively, p = 0.006). Conclusion: The V/M ratio was significantly lower in patients with diabetes compared to non-diabetics, even after correcting for obstructive coronary stenosis. The clinical value of the reduced V/M ratio in diabetic patients needs further investigation. Show less
Background: The role of change in fractional flow reserve derived from CT (FFRCT) across coronary stenoses (Delta FFRCT) in guiding downstream testing in patients with stable coronary artery... Show moreBackground: The role of change in fractional flow reserve derived from CT (FFRCT) across coronary stenoses (Delta FFRCT) in guiding downstream testing in patients with stable coronary artery disease (CAD) is unknown. Objectives: To investigate the incremental value of Delta FFRCT in predicting early revascularization and improving efficiency of catheter laboratory utilization. Materials: Patients with CAD on coronary CT angiography (CCTA) were enrolled in an international multicenter registry. Stenosis severity was assessed as per CAD-Reporting and Data System (CAD-RADS), and lesion-specific FFRCT was measured 2 cm distal to stenosis. Delta FFRCT was manually measured as the difference of FFRCT across visible stenosis. Results: Of 4730 patients (66 +/- 10 years; 34% female), 42.7% underwent ICA and 24.7% underwent early revascularization. AFFRCT remained an independent predictor for early revascularization (odds ratio per 0.05 increase [95% confidence interval], 1.31 [1.26-1.35]; p < 0.001) after adjusting for risk factors, stenosis features, and lesion-specific FFRCT. Among the 3 models (model 1: risk factors + stenosis type and location + CAD-RADS; model 2: model 1 + FFRCT; model 3: model 2 + AFFRCT), model 3 improved discrimination compared to model 2 (area under the curve, 0.87 [0.86-0.88] vs 0.85 [0.84-0.86]; p < 0.001), with the greatest incremental value for FFRCT 0.71-0.80. AFFRCT of 0.13 was the optimal cut-off as determined by the Youden index. In patients with CAD-RADS >3 and lesion-specific FFRCT <0.8, a diagnostic strategy incorporating AFFRCT >0.13, would potentially reduce ICA by 32.2% (1638-1110, p < 0.001) and improve the revascularization to ICA ratio from 65.2% to 73.1%. Conclusions: AFFRCT improves the discrimination of patients who underwent early revascularization compared to a standard diagnostic strategy of CCTA with FFRCT, particularly for those with FFRCT 0.71-0.80. AFFRCT has the potential to aid decision-making for ICA referral and improve efficiency of catheter laboratory utilization. Show less
Anastasius, M.; Maggiore, P.; Huang, A.L.; Blanke, P.; Patel, M.R.; Norgaard, B.L.; ... ; Leipsic, J. 2021
Background: CT coronary angiography (CTA) with Fractional Flow Reserve as determined by CT (FFRCT) is a safe alternative to invasive coronary angiography. A negative FFRCT has been shown to have... Show moreBackground: CT coronary angiography (CTA) with Fractional Flow Reserve as determined by CT (FFRCT) is a safe alternative to invasive coronary angiography. A negative FFRCT has been shown to have low cardiac event rates compared to those with a positive FFRCT. However, the clinical utility of FFRCT according to age is not known.Methods: Patients' in the ADVANCE (Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care) registry, were stratified into those >= 65 or <65 years of age. The impact of FFRCT on clinical decision-making, as assessed by patient age, was determined by evaluating patient management using CTA results alone, followed by site investigators submitting a report on the treatment plan based upon the newly provided FFRCT data. Outcomes at 1-year post CTA were assessed, including major adverse cardiovascular events (myocardial infarction, all-cause mortality or unplanned hospitalization for ACS leading to revascularisation) and total revascularisation. Positive FFRCT was deemed to be <= 0.8.Results: FFRCT was calculated in 1849 (40.6%) subjects aged <65 and 2704 (59.4%) >= 65 years of age. Subjects >= 65 years were more likely to have anatomic obstructive disease on CTA (>= 50% stenosis), compared to those aged <65 (69.7% and 73.2% respectively, p = 0.008). There was a similar graded increase in recommended and actual revascularisation with either CABG or PCI, with declining FFRCT strata for subjects above and below the age of 65. MACE and revascularisation rates were not significantly different for those >= or <65, regardless of FFRCT positivity or stenosis severity <50% or >= 50%. With a negative FFRCT result, and anatomical stenosis >= 50%, those >= and <65 years of age, had similar rates of MACE (0.2% for both, p = 0.1) and revascularisation (8.7% and 10.4% respectively p = 0.4).Logistic regression analysis, with age as a continuous variable, and adjustment for Diamond Forrester Risk, baseline FFRCT and treatment (CABG, PCI, medical therapy), indicated a statistically significant, but small increase in the odds of a MACE event with increasing age (OR 1.04, 95% CI 1.006-1.08, p = 0.02). Amongst patients with a FFRCT > 0.80, there was no effect of age on the odds of revascularisation.Conclusion: The findings of this study point to a low risk of MACE events or need for revascularisation in those aged >= or <65 with a FFRCT>0.80, despite the higher incidence of anatomic obstructive CAD in those >= 65 years. The findings show the clinical usefulness and outcomes of FFRCT are largely constant regardless of age. Show less
Background: The ADVANCE registry is a large prospective study of outcomes and resource utilization in patients undergoing coronary computed tomography angiography (CCTA) and CT-based fractional... Show moreBackground: The ADVANCE registry is a large prospective study of outcomes and resource utilization in patients undergoing coronary computed tomography angiography (CCTA) and CT-based fractional flow reserve (FFRCT). As experience with new technologies and practices develops over time, we investigated temporal changes in the use of FERCT within the ADVANCE registry.Methods: 5083 patients with coronary artery disease (CAD) on CCTA were prospectively enrolled in the ADVANCE registry and were divided into 3 equally sized cohorts based on the temporal order of enrollment per site. Demographics, CCTA and FERCT findings, and clinical outcomes through 1-year follow-up, were recorded and compared between tertiles.Results: The number of patients with a >= 70% stenosis on CCTA was similar over time (33.6%, 30.9%, and 33.8% for cohort 1-3). The rate of positive FFRCT <= 0.80 was higher for cohorts 2 (67.3%) and 3 (74.6%) than for cohort 1 (57.1%, p < 0.001). Invasive FFR rates decreased from 25.8% to 22.4% between cohort 1 and 3 (p = 0.023). Moreover, patients with a FFRCT <= 0.80 were less frequently referred for invasive coronary angiography (ICA) (from 62.9% to 52.9%, p < 0.001), and underwent fewer revascularizations between cohort 1 and 3 (from 41.9% to 32.0%, p < 0.001). The prevalence of major events was low (1.2%) and similar between cohorts.Conclusions: Growing experience with FFRCT improved the likelihood of identifying hemodynamically significant CAD and safely reduced the need for ICA and revascularization in patients with anatomically significant disease even in the instance of an abnormal FFRCT. Show less
OBJECTIVES This study is to determine the management and clinical outcomes of patients investigated with coronary computed tomography angiography (CCTA)-derived fractional flow reserve (FFRCT)... Show moreOBJECTIVES This study is to determine the management and clinical outcomes of patients investigated with coronary computed tomography angiography (CCTA)-derived fractional flow reserve (FFRCT) according to sex.BACKGROUND Women are underdiagnosed with conventional ischemia testing, have lower rates of obstructive coronary artery disease (CAD) at invasive coronary angiography (ICA), yet higher mortality compared to men. Whether FFRCT improves sex-based patient management decisions compared to CCTA alone is unknown.METHODS Subjects with symptoms and CAD on CCTA were enrolled (2015 to 2017). Demographics, symptom status, CCTA anatomy, coronary volume to myocardial mass ratio (V/M), lowest FFRCT values, and management plans were captured. Endpoints included reclassification rate between CCTA and FFRCT management plans, incidence of ICA demonstrating obstructive CAD ($50% stenosis) and revascularization rates.RESULTS A total of 4,737 patients (n = 1,603 females, 33.8%) underwent CCTA and FFRCT. Women were older (age 68 +/- 10 years vs. 65 +/- 10 years; p < 0.0001) with more atypical symptoms (41.5% vs. 33.9%; p < 0.0001). Women had less obstructive CAD (65.4% vs. 74.7%; p < 0.0001) at CCTA, higher FFRCT (0.76 +/- 0.10 vs. 0.73 +/- 0.10; p < 0.0001), and lower likelihood of positive FFRCT <= 0.80 for the same degree stenosis (p < 0.0001). A positive FFRCT <= 0.80 resulted in equal referral to ICA (n = 510 [54.5%] vs. n = 1,249 [56.5%]; p = 0.31), but more nonobstructive CAD (n = 208 [32.1%] vs. n = 354 [24.5%]; p = 0.0003) and less revascularization (n = 294 [31.4%] vs. n = 800 [36.2%]; p < 0.0001) in women, unless the FFRCT was #0.75 where revascularization rates were similar (n = 253 [41.9%] vs. n = 715 [46.4%]; p = 0.06). Women have a higher V/M ratio (26.17 +/- 7.58 mm(3)/g vs. 24.76 +/- 7.22 mm(3)/g; p < 0.0001) that is associated with higher FFRCT independent of degree stenosis (p < 0.001). Predictors of revascularization included stenosis severity, FFRCT, symptoms, and V/M ratio (p < 0.001) but not female sex (p = 0.284).CONCLUSIONS FFRCT differs between the sexes, as women have a higher FFRCT for the same degree of stenosis. In FFRCT-positive CAD, women have less obstructive CAD at ICA and less revascularization, which is associated with higher V/M ratio. The findings suggest that CAD and FFRCT variations by sex need specific interpretation as these differences may affect therapeutic decision making and clinical outcomes. (Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care [ADVANCE]; NCT02499679) (C) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. Show less
Harikane, Y.; Ouchi, M.; Inoue, A.K.; Matsuoka, Y.; Tamura, Y.; Bakx, T.; ... ; Vallini, L. 2020
OBJECTIVES The 1-year data from the international ADVANCE (Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care) Registry of patients undergoing coronary computed tomography... Show moreOBJECTIVES The 1-year data from the international ADVANCE (Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care) Registry of patients undergoing coronary computed tomography angiography (CTA) was used to evaluate the relationship of fractional flow reserve derived from coronary CTA (FFRCT) with downstream care and clinical outcomes.BACKGROUND Guidelines for management of chest pain using noninvasive imaging pathways are based on short- to intermediate-term outcomes.METHODS Patients (N = 5,083) evaluated for clinically suspected coronary artery disease and in whom atherosclerosis was identified by coronary CTA were prospectively enrolled at 38 international sites from July 15, 2015, to October 20, 2017. Demographics, symptom status, coronary CTA and FFRCT findings and resultant site-based treatment plans, and clinical outcomes through 1 year were recorded and adjudicated by a blinded core laboratory. Major adverse cardiac events (MACE), death, myocardial infarction (MI), and acute coronary syndrome leading to urgent revascularization were captured.RESULTS At 1 year, 449 patients did not have follow-up data. Revascularization occurred in 1,208 (38.40%) patients with an FFRCT <= 0.80 and in 89 (5.60%) with an FFRCT >0.80 (relative risk [RR]: 6.87; 95% confidence interval [CI]: 5.59 to 8.45; p < 0.001). MACE occurred in 55 patients, 43 events occurred in patients with an FFRCT <= 0.80 and 12 occurred in those with an FFRCT >0.80 (RR: 1.81; 95% CI: 0.96 to 3.43; p = 0.06). Time to first event (all-cause death or MI) occurred in 38 (1.20%) patients with an FFRCT <= 0.80 compared with 10 (0.60%) patients with an FFRCT >0.80 (RR: 1.92; 95% CI: 0.96 to 3.85; p = 0.06). Time to first event (cardiovascular death or MI) occurred cardiovascular death or MI occurred more in patients with an FFRCT <= 0.80 compared with patients with an FFRCT >0.80 (25 [0.80%] vs. 3 [0.20%]; RR: 4.22; 95% CI: 1.28 to 13.95; p = 0.01).CONCLUSIONS The 1-year outcomes from the ADVANCE FFRCT Registry show low rates of events in all patients, with less revascularization and a trend toward lower MACE and significantly lower cardiovascular death or MI in patients with a negative FFRCT compared with patients with abnormal FFRCT values. (Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Wave [ADVANCE]; NCT02499679) (C) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. Show less
Background: Coronary computed tomography angiography (cCTA)-derived fractional flow reserve (FFRCT) is a promising diagnostic method for the evaluation of coronary artery disease (CAD). However,... Show moreBackground: Coronary computed tomography angiography (cCTA)-derived fractional flow reserve (FFRCT) is a promising diagnostic method for the evaluation of coronary artery disease (CAD). However, clinical data regarding FFRCT in Japan are scarce, so we assessed the clinical impact of using FFRCT in a Japanese population.Methods and Results: The ADVANCE registry is an international prospective FFRCT registry of patients suspected of CAD. Of 5,083 patients, 1,829 subjects enrolled from Japan were analyzed. Demographics, symptoms, cCTA, FFRCT, treatment strategy, and 90-day major cardiovascular events (MACE) were assessed. Reclassification of treatment strategy between cCTA alone and cCTA+ FFRCT occurred in 55.8% of site investigations and in 56.9% in the core laboratory analysis. Patients with positive FFR (FFRCT =0.80) were less likely to have non-obstructive disease on invasive coronary angiography than patients with negative FFR (FFRCT > 0.80) (20.5% vs. 46.1%, P=0.0001). After FFRCT, 67.0% of patients with positive results underwent revascularization, whereas 96.1% of patients with negative FFRCT were medically treated. MACE occurred in 5 patients with positive FFRCT, but none occurred in patients with negative FFRCT within 90 days.Conclusions: In this Japanese population, FFRCT modified the treatment strategy in more than half of the patients. FFRCT showed potential for stratifying patients suspected of CAD properly into invasive or non-invasive management pathways. Show less
