Wall shear stress-related plaque growth of lipid-rich plaques in human coronary arteries: an near-infrared spectroscopy and optical coherence tomography study.

AIMS: Low wall shear stress (WSS) is acknowledged to play a role in plaque development through its influence on local endothelial function. Also, lipid-rich plaques (LRPs) are associated with endothelial dysfunction. However, little is known about the interplay between WSS and the presence of lipids with respect to plaque progression. Therefore, we aimed to study the differences in WSS-related plaque progression between LRPs, non-LRPs, or plaque-free regions in human coronary arteries. METHODS AND RESULTS: In the present single-centre, prospective study, 40 patients who presented with an acute coronary syndrome successfully underwent near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) and optical coherence tomography (OCT) of at least one non-culprit vessel at baseline and completed a 1-year follow-up. WSS was computed applying computational fluid dynamics to a three-dimensional reconstruction of the coronary artery based on the fusion of the IVUS-segmented lumen with a CT-derived centreline, using invasive flow measurements as boundary conditions. For data analysis, each artery was divided into 1.5 mm/45° sectors. Plaque growth based on IVUS-derived percentage atheroma volume change was compared between LRPs, non-LRPs, and plaque-free wall segments, as assessed by both OCT and NIRS. Both NIRS- and OCT-detected lipid-rich sectors showed a significantly higher plaque progression than non-LRPs or plaque-free regions. Exposure to low WSS was associated with a higher plaque progression than exposure to mid or high WSS, even in the regions classified as a plaque-free wall. Furthermore, low WSS and the presence of lipids had a synergistic effect on plaque growth, resulting in the highest plaque progression in lipid-rich regions exposed to low shear stress. CONCLUSION: This study demonstrates that NIRS- and OCT-detected lipid-rich regions exposed to low WSS are subject to enhanced plaque growth over a 1-year follow-up. The presence of lipids and low WSS proves to have a synergistic effect on plaque growth.

Dynamic Myocardial Perfusion CT for the Detection of Hemodynamically Significant Coronary Artery Disease.

OBJECTIVES: In this international, multicenter study, using third-generation dual-source computed tomography (CT), we investigated the diagnostic performance of dynamic stress CT myocardial perfusion imaging (CT-MPI) in addition to coronary CT angiography (CTA) compared to invasive coronary angiography (ICA) and invasive fractional flow reserve (FFR). BACKGROUND: CT-MPI combined with coronary CTA integrates coronary artery anatomy with inducible myocardial ischemia, showing promising results for the diagnosis of hemodynamically significant coronary artery disease in single-center studies. METHODS: At 9 centers in Europe, Japan, and the United States, 132 patients scheduled for ICA were enrolled; 114 patients successfully completed coronary CTA, adenosine-stress dynamic CT-MPI, and ICA. Invasive FFR was performed in vessels with 25% to 90% stenosis. Data were analyzed by independent core laboratories. For the primary analysis, for each coronary artery the presence of hemodynamically significant obstruction was interpreted by coronary CTA with CT-MPI compared to coronary CTA alone, using an FFR of ≤0.80 and angiographic severity as reference. Territorial absolute myocardial blood flow (MBF) and relative MBF were compared using C-statistics. RESULTS: ICA and FFR identified hemodynamically significant stenoses in 74 of 289 coronary vessels (26%). Coronary CTA with ≥50% stenosis demonstrated a per-vessel sensitivity, specificity, and accuracy for the detection of hemodynamically significant stenosis of 96% (95% CI: 91%-100%), 72% (95% CI: 66%-78%), and 78% (95% CI: 73%-83%), respectively. Coronary CTA with CT-MPI showed a lower sensitivity (84%; 95% CI: 75%-92%) but higher specificity (89%; 95% CI: 85%-93%) and accuracy (88%; 95% CI: 84%-92%). The areas under the receiver-operating characteristic curve of absolute MBF and relative MBF were 0.79 (95% CI: 0.71-0.86) and 0.82 (95% CI: 0.74-0.88), respectively. The median dose-length product of CT-MPI and coronary CTA were 313 mGy·cm and 138 mGy·cm, respectively. CONCLUSIONS: Dynamic CT-MPI offers incremental diagnostic value over coronary CTA alone for the identification of hemodynamically significant coronary artery disease. Generalized results from this multicenter study encourage broader consideration of dynamic CT-MPI in clinical practice. (Dynamic Stress Perfusion CT for Detection of Inducible Myocardial Ischemia [SPECIFIC]; NCT02810795).

CT-derived fractional flow reserve (FFRct) for functional coronary artery evaluation in the follow-up of patients after heart transplantation.

OBJECTIVES: Invasively measured fractional flow reserve (FFR) is associated with outcome in heart transplant (HTx) patients. Coronary computed tomography angiography (CCTA)-derived FFR (FFRct) provides additional functional information from anatomical CT images. We describe the first use of FFRct in HTx patients. METHODS: HTx patients underwent CCTA with FFRct to screen for cardiac allograft vasculopathy. FFRct was measured distal to each coronary stenosis > 30% and FFRct ≤ 0.8 indicated hemodynamically significant stenosis. FFRct was also measured at the most distal location of each vessel. Overall distal FFRct was calculated as the mean of the distal values in the left, right, and circumflex coronary artery in each patient. RESULTS: Seventy-three patients (age 56 (42-65) years, 63% males) at 11 (8-16) years after HTx were included. Eighteen (25%) patients had a focal hemodynamically significant stenosis (stenosis > 30% with FFRct ≤ 0.8). In the 55 patients without a hemodynamically significant focal FFRct stenosis (FFRct > 0.80), the distal left anterior descending artery FFRct was < 0.90 in 74% of the patients and 10 (18%) patients had ≥ 1 coronary artery with a distal FFRct ≤ 0.8, including 1 with a distal FFRct ≤ 0.8 in all coronaries. Overall distal FFRct in patients without focal stenosis was 0.88 (0.86-0.91), 0.87 (0.86-0.90), and 0.88 (0.86-0.91) (median with 25th-75th percentile) at 5-9, 10-14, or ≥ 15 years post-transplantation, respectively (p = 0.93). CONCLUSIONS: FFRct performed on CCTA scans of HTx patients demonstrated that 25% of patients had a focal coronary stenosis with FFRct ≤ 0.8. Even without a focal stenosis, FFRct values are often abnormal in HTx patients. KEY POINTS: • This is the first report describing the use of FFRct in in heart transplant patients. • FFRct identifies patients after heart transplantation with hemodynamically significant coronary stenosis. • Even without a focal stenosis, FFRct values are often abnormal in heart transplant patients.

Clinical implementation of coronary computed tomography angiography for routine detection of cardiac allograft vasculopathy in heart transplant patients.

Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease that affects long-term outcomes in heart transplant (HTx) patients. We prospectively evaluated the feasibility of coronary computed tomography angiography (CCTA) for the detection of CAV during clinical implementation at our center. All consecutive HTx patients >4 years post-transplant were actively converted from myocardial perfusion imaging to CCTA for the annual assessment of CAV. Between February 2018 and May 2019, 129/172 (75%) HTx patients underwent a CCTA. Renal impairment (n = 21/43) was the most frequent reason for patients could not undergo CCTA. CCTA image quality was good-excellent in 118/129 (92%) patients, and the radiation dose was 2.1 (1.6-2.8) mSv. CCTA showed obstructive CAV in 19/129 (15%) patients. Thirteen (10%) patients underwent additional tests, of which 8 patients underwent coronary revascularization within 90 days of CCTA. After 1 year, 3 additional coronary angiograms were performed, resulting in one revascularization in a patient with known severe CAV who developed ventricular tachycardia. One myocardial infarction after coronary stenting and 2 non-cardiac deaths were observed. CCTA can be successfully implemented for routine detection of CAV with good image quality and low radiation dose. CCTA allows CAV evaluation with the limited need for additional invasive testing.

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.

Prognostic Value of Subclinical Coronary Artery Disease in Atrial Fibrillation Patients Identified by Coronary Computed Tomography Angiography.

Identifying coronary artery disease (CAD) in atrial fibrillation (AF) patients improves risk stratification and defines clinical management. However, the value of screening for subclinical CAD with cardiac CT in AF patients is unknown. Between 2011 and 2015, 94 consecutive patients without known or suspected CAD (66 (57-73) years, 68% male), who were referred for AF evaluation, underwent a noncontrast-enhanced coronary calcium scan and a coronary computed tomography angiography (CCTA) at our center. We retrospectively evaluated the coronary calcium score, the prevalence of obstructive CAD (≥50% stenosis) determined by CCTA, compared clinical management and 5-year outcome in patients with and without obstructive CAD on CCTA, and examined the potential impact of a coronary calcium score and obstructive CAD on CCTA as a manifestation of vascular disease on the CHA2Ds2VASc score and for the cardiovascular risk stratification of AF patients. The median coronary calcium score was 57 (0-275) and 24 patients (26%) had obstructive CAD on CCTA. At baseline, patients with obstructive CAD more often used statins than those without obstructive CAD (54% vs 26%, p = 0.011). After a median clinical follow-up of 2.4 (0.5-4.5) years, patients with obstructive CAD more frequently used oral anticoagulant and/or antiplatelet drugs, statins, angiotensin-II-receptor blockers and/or angiotensin-converting-enzyme inhibitors, and less often used class I antiarrhythmic drugs than patients without obstructive CAD (all p <0.050). After a median follow-up of 5.7 (4.8-6.8) years, mortality was higher in patients with obstructive CAD than in those without obstructive CAD (29% vs 11%, log-rank test: p = 0.034). Implementation of a coronary calcium score and/or obstructive CAD on CCTA elevated the CHA2Ds2VASc score and cardiovascular risk stratification in 42 patients (p <0.001) and 47 patients (p = 0.006), respectively. In conclusion, we observed a high prevalence of obstructive CAD on CCTA in AF patients without known or suspected CAD. AF patients with obstructive CAD were managed differently and had a worse prognosis than those without obstructive CAD. Cardiac CT could enhance cardiovascular risk stratification of AF patients.

Impact of machine-learning CT-derived fractional flow reserve for the diagnosis and management of coronary artery disease in the randomized CRESCENT trials.

OBJECTIVE: To determine the potential impact of on-site CT-derived fractional flow reserve (CT-FFR) on the diagnostic efficiency and effectiveness of coronary CT angiography (CCTA) in patients with obstructive coronary artery disease (CAD) on CCTA. METHODS: This observational cohort study included patients with suspected CAD who had been randomized to cardiac CT in the CRESCENT I and II trials. On-site CT-FFR was blindly performed in all patients with at least one ≥ 50% stenosis on CCTA and no exclusion criteria for CT-FFR. We retrospectively assessed the effect of adding CT-FFR to the CT protocol in patients with a stenosis ≥ 50% on CCTA in terms of diagnostic effectiveness, i.e., the number of additional tests required to determine the final diagnosis, reclassification of the initial management strategy, and invasive coronary angiography (ICA) efficiency, i.e., ICA rate without ≥ 50% CAD. RESULTS: Fifty-three patients out of the 372 patients (14%) had at least one ≥ 50% stenosis on CCTA of whom 42/53 patients (79%) had no exclusion criteria for CT-FFR. CT-FFR showed a hemodynamically significant stenosis (≤ 0.80) in 27/53 patients (51%). The availability of CT-FFR would have reduced the number of patients requiring additional testing by 57%-points compared with CCTA alone (37/53 vs. 7/53, p < 0.001). The initial management strategy would have changed for 30 patients (57%, p < 0.001). Reserving ICA for patients with a CT-FFR ≤ 0.80 would have reduced the number of ICA following CCTA by 13%-points (p = 0.016). CONCLUSION: Implementation of on-site CT-FFR may change management and improve diagnostic efficiency and effectiveness in patients with obstructive CAD on CCTA. KEY POINTS: • The availability of on-site CT-FFR in the diagnostic evaluation of patients with obstructive CAD on CCTA would have significantly reduced the number of patients requiring additional testing compared with CCTA alone. • The implementation of on-site CT-FFR would have changed the initial management strategy significantly in the patients with obstructive CAD on CCTA. • Restricting ICA to patients with a positive CT-FFR would have significantly reduced the ICA rate in patients with obstructive CAD on CCTA.

Comparison of the Diagnostic Performance of Coronary Computed Tomography Angiography-Derived Fractional Flow Reserve in Patients With Versus Without Diabetes Mellitus (from the MACHINE Consortium).

Coronary computed tomography angiography-derived fractional flow reserve (CT-FFR) is a noninvasive application to evaluate the hemodynamic impact of coronary artery disease by simulating invasively measured FFR based on CT data. CT-FFR is based on the assumption of a normal coronary microvascular response. We assessed the diagnostic performance of a machine-learning based application for on-site computation of CT-FFR in patients with and without diabetes mellitus with suspected coronary artery disease. The study population included 75 diabetic and 276 nondiabetic patients who were enrolled in the MACHINE consortium. The overall diagnostic performance of coronary CT angiography alone and in combination with CT-FFR were analyzed with direct invasive FFR comparison in 110 coronary vessels of the diabetic group and in 415 coronary vessels of the nondiabetic group. Per-vessel discrimination of lesion-specific ischemia by CT-FFR was assessed by the area under the receiver operating characteristic curves. The overall diagnostic accuracy of CT-FFR in diabetic patients was 83% and in nondiabetic patients 75% (p = 0.088), showing improvement over the diagnostic accuracy of coronary CT angiography, which was 58% and 65% (p = 0.223), respectively. In addition, the diagnostic accuracy of CT-FFR was similar between diabetic and nondiabetic patients per stratified CT-FFR group (CT-FFR < 0.6, 0.6 to 0.69, 0.7 to 0.79, 0.8 to 0.89, ≥0.9). The area under the curves for diabetic and nondiabetic patients were also comparable, 0.88 and 0.82 (p = 0.113), respectively. In conclusion, on-site machine-learning CT-FFR analysis improved the diagnostic performance of coronary CT angiography and accurately discriminated lesion-specific ischemia in both diabetic and nondiabetic patients suspected of coronary artery disease.

Comprehensive Cardiac CT With Myocardial Perfusion Imaging Versus Functional Testing in Suspected Coronary Artery Disease: The Multicenter, Randomized CRESCENT-II Trial.

OBJECTIVES: This study sought to assess the effectiveness, efficiency, and safety of a tiered, comprehensive cardiac computed tomography (CT) protocol in comparison with functional testing. BACKGROUND: Although CT angiography accurately rules out coronary artery disease (CAD), incorporation of CT myocardial perfusion imaging as part of a tiered diagnostic approach could improve the clinical value and efficiency of cardiac CT in the diagnostic work-up of patients with angina pectoris. METHODS: Between July 2013 and November 2015, 268 patients (mean age 58 years; 49% female) with stable angina (mean pre-test probability 54%) were prospectively randomized between cardiac CT and standard guideline-directed functional testing (95% exercise electrocardiography). The tiered cardiac CT protocol included a calcium scan, followed by CT angiography if calcium was detected. Patients with ≥50% stenosis on CT angiography underwent CT myocardial perfusion imaging. RESULTS: By 6 months, the primary endpoint, the rate of invasive coronary angiograms without a European Society of Cardiology class I indication for revascularization, was lower in the CT group than in the functional testing group (2 of 130 [1.5%] vs. 10 of 138 [7.2%]; p = 0.035), whereas the proportion of invasive angiograms with a revascularization indication was higher (88% vs. 50%; p = 0.017). The median duration until the final diagnosis was 0 (0 of 0) days in the CT group and 0 (0 of 17) in the functional testing group (p < 0.001). Overall, 13% of patients randomized to CT required further testing, compared with 37% in the functional testing group (p < 0.001). The adverse event rate was similar (3% vs. 3%; p = 1.000), although the median cumulative radiation dose was higher for the CT group (3.1 mSv [interquartile range: 1.6 to 7.8] vs. 0 mSv [interquartile range: 0.0 to 7.1]; p < 0.001). CONCLUSIONS: In patients with suspected stable CAD, a tiered cardiac CT protocol with dynamic perfusion imaging offers a fast and efficient alternative to functional testing. (Comprehensive Cardiac CT Versus Exercise Testing in Suspected Coronary Artery Disease 2 [CRESCENT2]; NCT02291484).

Myocardial fibrosis and pro-fibrotic markers in end-stage heart failure patients during continuous-flow left ventricular assist device support.

OBJECTIVES: During support with a left ventricular assist device (LVAD), partial reverse remodelling takes place in which fibrosis plays an important role. In this study, we analysed the histological changes and expression of fibrotic markers in patients with advanced heart failure (HF) during continuous-flow LVAD (cf-LVAD) support. METHODS: In 25 patients, myocardial tissue at the time of LVAD implantation (pre-LVAD) was compared with tissue from the explanted left ventricle (post-LVAD). Interstitial fibrosis and cardiomyocyte size were analysed pre- and post-LVAD. Plasma was obtained from all patients before and during LVAD support. Plasma levels, cardiac mRNA and protein expression of brain natriuretic peptide (BNP), galectin-3 (Gal-3), connective tissue growth factor (CTGF), osteopontin (OPN) and transforming growth factor ß-1 were determined. RESULTS: Fibrosis increased during cf-LVAD unloading (P < 0.05). Cardiomyocytes elongated (P < 0.05), whereas cross-sectional area did not change. BNP, Gal-3, CTGF and OPN were significantly elevated pre-LVAD in comparison with controls. BNP decreased significantly after 1 month of cf-LVAD support (P < 0.001) to near-normal levels. Pro-fibrotic markers remained elevated in comparison with controls. CONCLUSIONS: cf-LVAD support is associated with lengthening of cardiomyocytes, without alterations in diameter size. Remarkably, myocardial fibrosis increased as well as circulating pro-fibrotic markers. Whether the morphological changes are a direct effect of reduced pulsatility during cf-LVAD support or due to HF progression requires further investigation.

Circulating growth differentiation factor-15 correlates with myocardial fibrosis in patients with non-ischaemic dilated cardiomyopathy and decreases rapidly after left ventricular assist device support.

AIMS: Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine and is emerging as a biomarker of cardiac remodelling. Left ventricular assist devices (LVADs) provide unloading of the left ventricle, resulting in partial reverse remodelling. Our aim was to study GDF-15 in patients with a non-ischaemic dilated cardiomyopathy (DCM) during LVAD support. METHODS AND RESULTS: We analysed circulating GDF-15 in 30 patients before and 1, 3, and 6 months after LVAD implantation and before heart transplantation or explantation. In addition, mRNA and protein expression of GDF-15 were evaluated in myocardial tissue obtained prior to and after LVAD support. Circulating GDF-15 was significantly higher before LVAD implantation as compared with healthy controls (P < 0.001). After 1 month of mechanical support, GDF-15 levels were significantly decreased compared with pre-implantation levels (P < 0.001) and remained stable thereafter. Circulating GDF-15 was significantly correlated with kidney function and the severity of myocardial fibrosis. Interestingly, GDF-15 mRNA and protein expression in the myocardium were hardly detectable. CONCLUSIONS: High circulating levels of GDF-15 in patients with end-stage non-ischaemic DCM correlate with myocardial fibrosis and kidney function and decline strongly after 1 month of mechanical unloading, remaining stable thereafter. However, cardiac mRNA and protein expression of GDF-15 are very low, suggesting that the heart is not an important source of GDF-15 production in these patients.