Prognostic Value of Coronary CT Angiography-derived Fractional Flow Reserve on 3-year Outcomes in Patients with Stable Angina.

Background The prognostic value of coronary CT angiography (CTA)-derived fractional flow reserve (FFR) beyond 1-year outcomes and in patients with high levels of coronary artery calcium (CAC) is uncertain. Purpose To assess the prognostic value of coronary CTA-derived FFR test results on 3-year clinical outcomes in patients with coronary stenosis and among a subgroup of patients with high levels of CAC. Materials and Methods This study represents a 3-year follow-up of patients with new-onset stable angina pectoris who were consecutively enrolled in the Assessing Diagnostic Value of Noninvasive CT-FFR in Coronary Care, known as ADVANCE (ClinicalTrials.gov: NCT02499679) registry, between December 2015 and October 2017 at three Danish sites. A high CAC was defined as an Agatston score of at least 400. A lesion-specific coronary CTA-derived FFR value of 2 cm with distal-to-stenosis value at or below 0.80 represented an abnormal test result. The primary end point was a composite of all-cause death and nonfatal spontaneous myocardial infarction. Event rates were estimated using the one-sample binomial model, and relative risk was compared between participants stratified by results of coronary CTA-derived FFR. Results This study included 900 participants: 523 participants with normal results (mean age, 64 years ± 9.6 [SD]; 318 male participants) and 377 with abnormal results from coronary CTA-derived FFR (mean age, 65 years ± 9.6; 264 male participants). The primary end point occurred in 11 of 523 (2.1%) and 25 of 377 (6.6%) participants with normal and abnormal coronary CTA-derived FFR results, respectively (relative risk, 3.1; 95% CI: 1.6, 6.3; P < .001). In participants with high CAC, the primary end point occurred in four of 182 (2.2%) and 19 of 212 (9.0%) participants with normal and abnormal coronary CTA-derived FFR results, respectively (relative risk, 4.1; 95% CI: 1.4, 11.8; P = .001). Conclusion In individuals with stable angina, a normal coronary CTA-derived FFR test result identified participants with a low 3-year risk of all-cause death or nonfatal spontaneous myocardial infarction, both in the overall cohort and in participants with high CAC scores. Clinical trial registration no. NCT02499679 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Sinitsyn in this issue.

Prognostic value of coronary computed tomography angiographic derived fractional flow reserve: a systematic review and meta-analysis.

OBJECTIVES: To obtain more powerful assessment of the prognostic value of fractional flow reserveCT testing we performed a systematic literature review and collaborative meta-analysis of studies that assessed clinical outcomes of CT-derived calculation of FFR (FFRCT) (HeartFlow) analysis in patients with stable coronary artery disease (CAD). METHODS: We searched PubMed and Web of Science electronic databases for published studies that evaluated clinical outcomes following fractional flow reserveCT testing between 1 January 2010 and 31 December 2020. The primary endpoint was defined as 'all-cause mortality (ACM) or myocardial infarction (MI)' at 12-month follow-up. Exploratory analyses were performed using major adverse cardiovascular events (MACEs, ACM+MI+unplanned revascularisation), ACM, MI, spontaneous MI or unplanned (>3 months) revascularisation as the endpoint. RESULTS: Five studies were identified including a total of 5460 patients eligible for meta-analyses. The primary endpoint occurred in 60 (1.1%) patients, 0.6% (13/2126) with FFRCT>0.80% and 1.4% (47/3334) with FFRCT ≤0.80 (relative risk (RR) 2.31 (95% CI 1.29 to 4.13), p=0.005). Likewise, MACE, MI, spontaneous MI or unplanned revascularisation occurred more frequently in patients with FFRCT ≤0.80 versus patients with FFRCT >0.80. Each 0.10-unit FFRCT reduction was associated with a greater risk of the primary endpoint (RR 1.67 (95% CI 1.47 to 1.87), p<0.001). CONCLUSIONS: The 12-month outcomes in patients with stable CAD show low rates of events in those with a negative FFRCT result, and lower risk of an unfavourable outcome in patients with a negative test result compared with patients with a positive test result. Moreover, the FFRCT numerical value was inversely associated with outcomes.

Reduction of Myocardial Infarction and All-Cause Mortality Associated to Statins in Patients Without Obstructive CAD.

OBJECTIVES: The aim of this work was to evaluate the prognostic impact of statin therapy in symptomatic patients without obstructive CAD. BACKGROUND: Information on the prognostic impact of post-coronary computed tomographic angiography (CTA) statin use in patients with no or nonobstructive coronary artery disease (CAD) is sparse. METHODS: Patients undergoing CTA with suspected CAD in western Denmark from 2008 to 2017 with <50% coronary stenoses were identified. Information on post-CTA use of statin therapy and cardiovascular events were obtained from national registries. RESULTS: The study included 33,552 patients, median aged 56 years, 58% female, with no (n = 19,669) or nonobstructive (n = 13,883) CAD and a median follow-up of 3.5 years. The absolute risk of the combined end point of myocardial infarction (MI) or all-cause mortality was directly associated with the CAD burden with an event rate/1,000 patient-years of 4.13 (95% CI: 3.69-4.61) in no, 7.74 (95% CI: 6.88-8.71) in mild (coronary artery calcium score [CACS] 0-99), 13.72 (95% CI: 11.61-16.23) in moderate (CACS 100-399), and 32.47 (95% CI: 26.25-40.16) in severe (CACS ≥400) nonobstructive CAD. Statin therapy was associated with a multivariable adjusted HR for MI and death of 0.52 (95% CI: 0.36-0.75) in no, 0.44 (95% CI: 0.32-0.62) in mild, 0.51 (95% CI: 0.34-0.75) in moderate, and 0.52 (95% CI: 0.32-0.86) in severe nonobstructive CAD. The estimated numbers needed to treat to prevent the primary end point were 92 (95% CI: 61-182) in no, 36 (95% CI: 26-58) in mild, 24 (95% CI: 15-61) in moderate, and 13 (95% CI: 7-86) in severe nonobstructive CAD. Residual confounding may persist, but not to an extent explaining all of the observed risk reduction associated with statin treatment. CONCLUSIONS: The risk of MI and all-cause mortality in patients without obstructive CAD is directly associated with the CAD burden. Statin therapy is associated with a reduction of MI and all-cause death across the spectrum of CAD, however, the absolute benefit of treatment is directionally proportional with the CAD burden.

Temporal changes in FFRCT-Guided Management of Coronary Artery Disease - Lessons from the ADVANCE Registry.

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 flow reserve (FFRCT). As experience with new technologies and practices develops over time, we investigated temporal changes in the use of FFRCT 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 FFRCT 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.

Carotid plaque composition by CT angiography in asymptomatic subjects: a head-to-head comparison to ultrasound.

OBJECTIVES: To describe carotid plaque composition by computed tomography angiography (CTA) in asymptomatic subjects and to compare this to carotid plaque assessment by ultrasound, coronary plaques by coronary CTA, and inflammatory biomarkers in plasma. METHODS: Middle-aged asymptomatic men, n = 43, without known cardiovascular disease and diabetes were included. Plaques in coronary and carotid arteries were evaluated using CTA. Total plaque volumes and plaque composition were assessed by a validated plaque analysis software. The 60% centile cut point was used to divide the population into low or high carotid total plaque volumes. The occurrence of carotid plaques and intima-media thickness (IMT) was estimated by ultrasound. RESULTS: Carotid plaque by ultrasound was undiagnosed in 13 of 28 participants (46%) compared to CTA. Participants having carotid plaques by ultrasound had significantly higher absolute volumes of all CTA-defined carotid plaque subtypes and a higher fraction of calcified plaque. A high carotid total plaque volume was independently associated with age (adjusted odds ratio (OR) 1.41 [95% confidence interval (CI) 1.14-1.74], p = 0.001), IMT (adjusted OR 2.26 [95% CI 1.10-4.65], p = 0.03), and D-dimer (adjusted OR 8.86 [95% CI 1.26-62.37], p = 0.03). All coronary plaque features were significantly higher in participants with a high carotid total plaque volume. CONCLUSION: The occurrence of carotid plaques in asymptomatic individuals is underestimated by ultrasound compared to plaque assessment by CTA. Carotid plaque composition by CTA is different in individuals with and without carotid plaques by ultrasound. KEY POINTS: • The occurrence of carotid plaques by ultrasound was underestimated in 46% of participants who had plaques by carotid CTA. • Participants with carotid plaques by ultrasound had higher volumes of all plaque subtypes and a higher calcified plaque component as determined by carotid CTA compared to participants without carotid plaques by ultrasound. • A high carotid total plaque volume was independently associated with age, intima-media thickness, and D-dimer.

Sex difference in fibrin clot lysability: Association with coronary plaque composition.

INTRODUCTION: Fibrin clot lysability is associated with development of cardiovascular disease (CVD). We evaluated sex-differences in fibrin clot lysability and the association with coronary plaque composition determined by computed tomography angiography (CTA). METHODS: Middle-aged citizens without known CVD were randomly selected from a national registry. A coronary CTA assessed volumes of calcified-, non-calcified-, low-density non-calcified-, and total- plaque using a validated plaque quantification software. A non-enhanced cardiac CT scan assessed the Agatston score. Fibrin structure properties were determined using turbidimetric methods. Plasma concentrations of C-reactive protein and fibrinogen were assessed. RESULTS: 138 individuals (71 women) participated. Men more frequently had coronary plaques compared to women, P < 0.05. Coronary plaque features were comparable between men and women, P > 0.05. Women with total plaque volume > 0 mm3 had lower fibrin clot lysability compared to women with total plaque volume = 0 mm3, adjusted difference [95% confidence interval] 10.28 [1.42-19.15], P = 0.02, and a fibrinogen-dependent lower fibrin clot lysability compared to men with and without coronary plaques, 6.82 [-2.67-16.31], P = 0.16, and 8.73 [-0.43-17.89], P = 0.06, respectively. Fibrinogen correlated with all the coronary plaque features (correlation coefficient r = 0.42-0.57) only in women with total plaque volume > 0 mm3, all P < 0.01. CONCLUSION: Asymptomatic women with coronary plaques assessed by coronary CTA have reduced fibrin clot lysability compared to both women without coronary plaques and men, suggesting a sex-dependent link between coronary atherosclerosis and fibrin clot lysability.

External validity of a cardiovascular screening including a coronary artery calcium examination in middle-aged individuals from the general population.

Background Coronary artery calcium is important in cardiovascular risk stratification, but this knowledge is based on studies with a significant selection bias. This study aims to evaluate the external validity of a screening programme including coronary artery calcium examination, and the association between coronary artery calcium and cardiovascular events. Design Multi-centre population based study. Methods Randomly selected middle-aged men and women ( N = 1751) free of cardiovascular disease were invited to the examination during 2009-2010. Participation rate in the examination was 70%. Participants ( n = 1227) and non-participants ( n = 524) were compared regarding: cardiovascular medical treatment, Charlson comorbidity index and socioeconomic status (evaluated by cohabitation, gross income and education). Study endpoints were cardiovascular events and mortality. Results Non-participants had a significant higher comorbidity ( p = 0.003) and a lower socioeconomic status ( p < 0.0001), while cardiovascular medical treatment was alike. Over a median follow-up time of 6.5 years the cardiovascular event and mortality rates were equal (6.7% vs. 6.4%, p = 0.80 and 0.4% vs. 0.5%, p = 0.76, respectively). Adjusted hazard ratio was 0.90 (95% confidence interval (CI) 0.63-1.37). Among participants, the extent of coronary artery calcium was significantly associated with increased risk of cardiovascular events (hazard ratio 1.92, 95% CI 1.03-3.54, hazard ratio 3.66, 95% CI 1.82-7.32, hazard ratio 6.51, 95% CI 3.17-13.36 for coronary artery calcium scores 1-99, 100-399, ≥400 AU, respectively). Conclusions Non-participants had a higher comorbidity index and a lower socioeconomic status, but the cardiovascular event and mortality rates were equal to those of participants. Thus, a screening programme including a coronary artery calcium examination had a high external validity regarding cardiovascular risk, but also a significant social imbalance.

Sex difference in clot lysability and association to coronary artery calcification.

BACKGROUND: Incidence and prevalence of cardiovascular disease (CVD) differ between sexes, and women experience CVD later than men. Changes in fibrin clot lysability are associated with CVD, and the present study addresses sex differences in fibrin clot lysability in asymptomatic middle-aged individuals and the relation to coronary artery calcification (CAC). METHODS: Participants free of morbidities and medication, N = 163, were randomly chosen from a national registry among citizens, 50 or 60 years of age, and were followed for 5 years. CAC was determined by the Agatston (Ag) score both at baseline and at follow-up. Based on the changes in Ag, the population was divided into two groups: ΔAg = 0 U or ΔAg > 0 U. Fibrin clot analyses were based on turbidimetric methods. RESULTS: At baseline, 116 women and 97 men were included; 84 women and 79 men completed the 5-year follow-up (77%). Independently of covariates, women with ΔAg > 0 had reduced mean (SD) fibrin lysability at follow-up, 40.2% (15.9), both in comparison to baseline, 47.8% (20.4), p = 0.001, to women with ΔAg = 0 U, 51.2% (24.5), p = 0.028, and to men with ΔAg > 0 U, 54.4% (21.0), p = 0.002. CONCLUSIONS: Fibrin clot lysability changes over time with considerable sex differences. Women with progression of CAC have reduced fibrin clot lysability compared to men, indicating a sex-specific association between morphological vessel wall changes and fibrin clot lysability.

High burden of coronary atherosclerosis in patients with a new diagnosis of type 2 diabetes.

PURPOSE: The purposes of this study were to compare the presence, extent and composition of coronary plaques in asymptomatic patients with newly diagnosed type 2 diabetes to age- and sex-matched controls. METHODS: Patients with newly diagnosed (<1 year) type 2 diabetes ( n = 44) and controls ( n = 44) underwent contrast-enhanced coronary computed tomography angiography. Advanced plaque analysis including total plaque volume and volumes of plaque components (calcified plaque and non-calcified plaque, including low-attenuation [low-density non-calcified plaque]) was performed using validated semi-automated software. RESULTS: Coronary artery calcification was more often seen in patients with type 2 diabetes (66%) versus controls (48%), p < 0.05. Both the absolute volume (median; interquartile range) of low-density non-calcified plaque (7.9 mm3; 0-50.5 mm3 vs 0; 0-34.3 mm3, p < 0.05) and the increase in low-density non-calcified plaque ratio in relation to total plaque volume ( τ = 0.5, p < 0.001) were significantly higher in patients with type 2 diabetes. More patients with type 2 diabetes had spotty calcification (31% vs 0%, p < 0.05). By multivariate analysis, the presence of any low-density non-calcified plaque was higher in males (odds ratio: 4.06, p < 0.05), who also demonstrated a larger low-density non-calcified plaque volume ( p < 0.001). The presence and extent of low-density non-calcified plaque increased with age, smoking, hypertension and hyperglycaemia, all p < 0.05. CONCLUSION: Asymptomatic patients with newly diagnosed type 2 diabetes had plaque features associated with increased vulnerability as compared with age- and sex-matched controls.

Factor VII-activating protease: sex-related association with coronary artery calcification.

: Factor VII-activating protease (FSAP) may regulate development of cardiovascular disease (CVD). We evaluated sex differences in FSAP measures and examined the association between FSAP and coronary artery calcification (CAC) in a middle-aged population. Participants were randomly selected citizens aged 50 or 60 without CVD, diabetes mellitus, Marburg I polymorphism, or hormone replacement therapy (HRT). FSAP protein concentration (total FSAP), FSAP urokinase-activating capacity (FSAP GP), and FSAP GP/total FSAP (specific FSAP activity) were measured. Cardiac computed tomography (CT) determined the Agatston score, dividing the study population in three groups: (1) Agatston score = 0 U, (2) Agatston score = 1-99 U, or (3) Agatston score more than 99 U. A total of 134 women and 116 men were included. Total FSAP, FSAP GP, and specific FSAP activity were independently higher in women (97.4%, 81.1%, 0.84, respectively) compared with men (87.5%, 68.7%, 0.79, respectively) (P < 0.001). In women, total FSAP was significantly different between (3) Agatston score (111.5%) and (1) Agatston score (95.4%), respectively, (2) Agatston score (96.8%), (P < 0.05). Also, the specific activity of FSAP was significantly different between (3) Agatston score (0.77) and (1) Agatston score (0.85), respectively, (2) Agatston score (0.86) (P < 0.05). No difference in FSAP measures was observed in men. FSAP measures are higher in women compared with age-matched men. The extent of CAC in women is positively associated with total FSAP, but negatively associated with the specific activity of FSAP suggesting that FSAP may play a role in the evolution of CVD in women.

An ELISA for the quantitation of von Willebrand factor: osteoprotegerin complexes in plasma.

BACKGROUND: Von Willebrand factor (VWF) is pivotal in arterial thrombosis, and osteoprotegerin (OPG) is besides being a bone protein also related to cardiovascular diseases. OPG can bind VWF, but the significance of this interaction is not known. OBJECTIVES: The aim was to develop an assay for measurement of von Willebrand factor-osteoprotegerin complex (VWF:OPG) in human plasma. Furthermore, the significance of VWF:OPG complex as a marker of cardiovascular disease (CVD) was evaluated. PATIENTS/METHODS: A sandwich ELISA for quantification of VWF:OPG was developed using a polyclonal rabbit anti-human VWF capturing antibody and a monoclonal anti-human OPG detecting antibody. Samples were quantified relative to a standard curve obtained from dilutions of a plasma pool from healthy individuals. The assay was evaluated in two groups of patients with CVD and two groups of asymptomatic individuals with and without documented coronary calcification (total n=118). RESULTS AND CONCLUSIONS: The assay detected VWF:OPG complexes in human plasma, while no significant signal was observed when testing solutions containing VWF or recombinant OPG alone. Importantly, the ELISA assay was able to detect in vitro formed complexes between human VWF and recombinant OPG in a dose-dependent manner. There was a large inter-individual variation in plasma VWF:OPG levels, but we found no significant differences in the level of VWF:OPG complexes between the four groups. Thus, we conclude that increasing OPG plasma levels in atherosclerotic CVD are not derived from increased levels of complexed form of VWF and OPG, but are more likely due to increased amounts of OPG secreted into the circulation.