Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development.

Coronary artery disease (CAD) remains the leading cause of adult mortality globally. Targeting known modifiable risk factors has had substantial benefit, but there remains a need for new approaches. Improvements in invasive and noninvasive imaging techniques have enabled an increasing recognition of distinct quantitative phenotypes of coronary atherosclerosis that are prognostically relevant. There are marked differences in plaque phenotype, from the high-risk, lipid-rich, thin-capped atheroma to the low-risk, quiescent, eccentric, nonobstructive calcified plaque. Such distinct phenotypes reflect different pathophysiologic pathways and are associated with different risks for acute ischemic events. Noninvasive coronary imaging techniques, such as computed tomography, positron emission tomography, and coronary magnetic resonance imaging, have major potential to accelerate cardiovascular drug development, which has been affected by the high costs and protracted timelines of cardiovascular outcome trials. This may be achieved through enrichment of high-risk phenotypes with higher event rates or as primary end points of drug efficacy, at least in phase 2 trials, in a manner historically performed through intravascular coronary imaging studies. Herein, we provide a comprehensive review of the current technology available and its application in clinical trials, including implications for sample size requirements, as well as potential limitations. In its effort to accelerate drug development, the US Food and Drug Administration has approved surrogate end points for 120 conditions, but not for CAD. There are robust data showing the beneficial effects of drugs, including statins, on CAD progression and plaque stabilization in a manner that correlates with established clinical end points of mortality and major adverse cardiovascular events. This, together with a clear mechanistic rationale for using imaging as a surrogate CAD end point, makes it timely for CAD imaging end points to be considered. We discuss the importance of global consensus on these imaging end points and protocols and partnership with regulatory bodies to build a more informed, sustainable staged pathway for novel therapies.

Inter-software and inter-scan variability in measurement of epicardial adipose tissue: a three-way comparison of a research-specific, a freeware and a coronary application software platform.

OBJECTIVES: Epicardial adipose tissue (EAT) is a proposed marker of cardiovascular risk; however, clinical application may be limited by variability in post-processing software platforms. We assessed inter-vendor agreement of EAT volume (EATv) and attenuation on both contrast-enhanced (CE) and non-contrast CT (NCT) using a standard coronary CT reporting software (Vitrea), an EAT research-specific software (QFAT) and a freeware imaging software (OsiriX). METHODS: Seventy-six consecutive patients undergoing simultaneous CE and NCT had complete volumetric EAT measurement. Between-software, within-software NCT vs. CE, and inter- and intra-observer agreement were evaluated with analysis by ANOVA (with post hoc adjustment), Bland-Altman with 95% levels of agreement (LoA) and intraclass correlation coefficient (ICC). RESULTS: Mean EATv (freeware 53 ± 31 mL vs. research 93 ± 43 mL vs. coronary 157 ± 64 mL) and attenuation (freeware - 72 ± 25 HU vs. research - 75 ± 3 HU vs. coronary - 61 ± 10 HU) were significantly different between all vendors (ANOVA p < 0.001). EATv was consistently higher in NCT vs. CE for all software packages, with most reproducibility found in research software (bias 26 mL, 95% LoA: 2 to 56 mL), compared to freeware (bias 11 mL 95% LoA: - 46 mL to 69 mL) and coronary software (bias 10 mL 95% LoA: - 127 to 147 mL). Research software had more comparable NCT vs. CE attenuation (- 75 vs. - 72 HU) compared to freeware (- 72 vs. - 57 HU) and coronary (- 61 vs. - 39 HU). Excellent inter-observer agreement was seen with research (ICC 0.98) compared to freeware (ICC 0.73) and coronary software (ICC 0.75) with narrow LoA on Bland-Altman analysis. CONCLUSION: There are significant inter-vendor differences in EAT assessment. Our study suggests that research-specific software has better agreement and reproducibility compared to freeware or coronary software platforms. KEY POINTS: • There are significant differences between EAT volume and attenuation values between software platforms, regardless of scan type. • Non-contrast scans routinely have higher mean EAT volume and attenuation; however, this finding is only consistently seen with research-specific software. • Of the three analyzed packages, research-specific software demonstrates the highest reproducibility, agreement, and reliability for both inter-scan and inter-observer agreement.

Inflammation in Coronary Atherosclerosis and Its Therapeutic Implications.

Atherosclerotic coronary artery disease has a complex pathogenesis which extends beyond cholesterol intimal infiltration. It involves chronic inflammation of the coronary artery wall driven by systemic and local activation of both the adaptive and innate immune systems, which can ultimately result in the rupture or erosion of atherosclerotic plaque, leading to thrombosis and myocardial infarction (MI). Despite current best practice care, including the widespread use of cholesterol-lowering statins, atherothrombotic cardiovascular events recur at alarming rates post-MI. To a large extent, this reflects residual inflammation that is not adequately controlled by contemporary treatment. Consequently, there has been increasing interest in the pharmacological targeting of inflammation to improve outcomes in atherosclerotic cardiovascular disease. This has comprised both novel pathway-specific agents, most notably the anti-interleukin-1 beta monoclonal antibody, canakinumab, and the repurposing of established, broad-acting drugs, such as colchicine, that are already approved for the management of other inflammatory conditions. Here we discuss the importance of inflammation in mediating atherosclerosis and its complications and provide a timely update on "new" and "old" anti-inflammatory therapies currently being investigated to target it.

Assessing the Impact of Colchicine on Coronary Plaque Phenotype After Myocardial Infarction with Optical Coherence Tomography: Rationale and Design of the COCOMO-ACS Study.

INTRODUCTION: Recurrent event rates after myocardial infarction (MI) remain unacceptably high, in part because of the continued growth and destabilization of residual coronary atherosclerotic plaques, which may occur despite lipid-lowering therapy. Inflammation is an important contributor to this ongoing risk. Recent studies have shown that the broad-acting anti-inflammatory agent, colchicine, may reduce adverse cardiovascular events in patients post-MI, although the mechanistic basis for this remains unclear. Advances in endovascular arterial wall imaging have allowed detailed characterization of the burden and compositional phenotype of coronary plaque, along with its natural history and responsiveness to treatment. One such example has been the use of optical coherence tomography (OCT) to demonstrate the plaque-stabilizing effects of statins on both fibrous cap thickness and the size of lipid pools within plaque. METHODS: The Phase 2, multi-centre, double-blind colchicine for coronary plaque modification in acute coronary syndrome (COCOMO-ACS) study will evaluate the effect of colchicine 0.5 mg daily on coronary plaque features using serial OCT imaging in patients following MI. Recruitment for the trial has been completed with 64 participants with non-ST elevation MI randomized 1:1 to colchicine or placebo in addition to guideline recommended therapies, including high-intensity statins. The primary endpoint is the effect of colchicine on the minimal fibrous cap thickness of non-culprit plaque over an 18-month period. The COCOMO-ACS study will determine whether addition of colchicine 0.5 mg daily to standard post-MI treatment has incremental benefits on high-risk features of coronary artery plaques. If confirmed, this will provide new mechanistic insights into how colchicine may confer clinical benefits in patients with atherosclerotic cardiovascular disease. TRIAL REGISTRATION: ANZCTR trial registration number: ACTRN12618000809235. Date of trial registration: 11th of May 2018.

Metabolic syndrome, fatty liver, and artificial intelligence-based epicardial adipose tissue measures predict long-term risk of cardiac events: a prospective study.

BACKGROUND: We sought to evaluate the association of metabolic syndrome (MetS) and computed tomography (CT)-derived cardiometabolic biomarkers (non-alcoholic fatty liver disease [NAFLD] and epicardial adipose tissue [EAT] measures) with long-term risk of major adverse cardiovascular events (MACE) in asymptomatic individuals. METHODS: This was a post-hoc analysis of the prospective EISNER (Early-Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) study of participants who underwent baseline coronary artery calcium (CAC) scoring CT and 14-year follow-up for MACE (myocardial infarction, late revascularization, or cardiac death). EAT volume (cm3) and attenuation (Hounsfield units [HU]) were quantified from CT using fully automated deep learning software (< 30 s per case). NAFLD was defined as liver-to-spleen attenuation ratio < 1.0 and/or average liver attenuation < 40 HU. RESULTS: In the final population of 2068 participants (59% males, 56 ± 9 years), those with MetS (n = 280;13.5%) had a greater prevalence of NAFLD (26.0% vs. 9.9%), higher EAT volume (114.1 cm3 vs. 73.7 cm3), and lower EAT attenuation (-76.9 HU vs. -73.4 HU; all p < 0.001) compared to those without MetS. At 14 ± 3 years, MACE occurred in 223 (10.8%) participants. In multivariable Cox regression, MetS was associated with increased risk of MACE (HR 1.58 [95% CI 1.10-2.27], p = 0.01) independently of CAC score; however, not after adjustment for EAT measures (p = 0.27). In a separate Cox analysis, NAFLD predicted MACE (HR 1.78 [95% CI 1.21-2.61], p = 0.003) independently of MetS, CAC score, and EAT measures. Addition of EAT volume to current risk assessment tools resulted in significant net reclassification improvement for MACE (22% over ASCVD risk score; 17% over ASCVD risk score plus CAC score). CONCLUSIONS: MetS, NAFLD, and artificial intelligence-based EAT measures predict long-term MACE risk in asymptomatic individuals. Imaging biomarkers of cardiometabolic disease have the potential for integration into routine reporting of CAC scoring CT to enhance cardiovascular risk stratification. Trial registration NCT00927693.

Quantitative and Qualitative Coronary Plaque Assessment Using Computed Tomography Coronary Angiography: A Comparison With Intravascular Ultrasound.

BACKGROUND: To compare computed tomography coronary angiography (CTCA) with intravascular ultrasound (IVUS) in quantitative and qualitative plaque assessment. METHODS: Patients who underwent IVUS and CTCA within 3 months for suspected coronary artery disease were retrospectively studied. Plaque volumes on CTCA were quantified manually and with automated-software and were compared to IVUS. High-risk plaque features were compared between CTCA and IVUS. RESULTS: There were 769 slices in 32 vessels (27 patients). Manual plaque quantification on CTCA was comparable to IVUS per slice (mean difference of 0.06±0.07, p=0.44; Bland-Altman 95% limits of agreement -2.19-2.08 mm3, bias of -0.06mm3) and per vessel (3.1mm3 ± -2.85mm3, p=0.92). In contrast, there was significant difference between automated-software and IVUS per slice (2.3±0.09mm3, p<0.001; 95% LoA -6.78 to 2.25mm3, bias of -2.2mm3) and per vessel (33.04±10.3 mm3, p<0.01). The sensitivity, specificity, positive and negative predictive value of CTCA to detect plaques that had features of echo-attenuation on IVUS was 93.3%, 99.6%, 93.3% and 99.6% respectively. The association of ≥2 high-risk plaque features on CTCA with echo attenuation (EA) plaque features on IVUS was excellent (86.7%, 99.6%, 92.9% and 99.2%). In comparison, the association of high-risk plaque features on CTCA and plaques with echo-lucency on IVUS was only modest. CONCLUSION: Plaque volume quantification by manual CTCA method is accurate when compared to IVUS. The presence of at least two high-risk plaque features on CTCA is associated with plaque features of echo attenuation on IVUS.

Perivascular Adipose Tissue and Coronary Atherosclerosis: from Biology to Imaging Phenotyping.

PURPOSE OF REVIEW: Perivascular adipose tissue (PVAT) has a complex, bidirectional relationship with the vascular wall. In disease states, PVAT secretes pro-inflammatory adipocytokines which may contribute to atherosclerosis. Recent evidence demonstrates that pericoronary adipose tissue (PCAT) may also function as a sensor of coronary inflammation. This review details PVAT biology and its clinical translation to current imaging phenotyping. RECENT FINDINGS: PCAT attenuation derived from routine coronary computed tomography (CT) angiography is a novel noninvasive imaging biomarker of coronary inflammation. Pro-inflammatory cytokines released from the arterial wall diffuse directly into the surrounding PCAT and inhibit adipocyte lipid accumulation in a paracrine manner. This can be detected as an increased PCAT CT attenuation, a metric which associates with high-risk plaque features and independently predicts cardiac mortality. There is also evidence that PCAT attenuation relates to coronary plaque progression and is modified by systemic anti-inflammatory therapies. Due to its proximity to the coronary arteries, PCAT has emerged as an important fat depot in cardiovascular research. PCAT CT attenuation has the potential to improve cardiovascular risk stratification, and future clinical studies should examine its role in guiding targeted medical therapy.

Application of the DILEMMA score to improve lesion selection for invasive physiological assessment.

OBJECTIVES: We sought to assess the validity of the DILEMMA score against instantaneous wave-free ratio (iFR) and evaluate its utility in rationalizing the number of patients referred for invasive physiological assessment. BACKGROUND: The DILEMMA score is a validated angiographic scoring tool incorporating minimal lumen diameter, lesion length and subtended myocardial area that has been shown to predict the functional significance of lesions as assessed by fractional flow reserve (FFR). METHODS: Patients in the DEFINE-FLAIR study who had coronary stenosis of intermediate severity were randomized to either FFR or iFR. DILEMMA score was calculated retrospectively on a subset of this cohort by operators blinded to FFR or iFR values. RESULTS: Three hundred and forty-six lesions (181 assessed by FFR; 165 by iFR) from 259 patients (mean age 66.0 years, 79% male) were included. A DILEMMA score ≤ 2 had a negative predictive value of 96.3% and 95.7% for identifying lesions with FFR >0.80 and iFR >0.89, respectively. A DILEMMA score ≥ 9 had a positive predictive value of 88.9% and 100% for identifying lesions with FFR ≤0.80 and iFR ≤0.89, respectively. The receiver operating characteristic area under the curve values for DILEMMA score to predict FFR ≤0.80 and iFR ≤0.89 were 0.83 (95% CI 0.77-0.90) and 0.82 (0.75-0.89) respectively. A DILEMMA score ≤ 2 or ≥9 occurred in 172 of the 346 lesions (49.7%). CONCLUSIONS: Using DILEMMA score in patients with coronary stenosis of intermediate severity may reduce the need for pressure wire use, offering potential cost-savings and minimizing the risks associated with invasive physiological lesion assessment.

Diagnostic Performance of Transluminal Attenuation Gradient and Noninvasive Fractional Flow Reserve Derived from 320-Detector Row CT Angiography to Diagnose Hemodynamically Significant Coronary Stenosis: An NXT Substudy.

PURPOSE: To compare the diagnostic performance of 320-detector row computed tomography (CT) coronary angiography-derived computed fractional flow reserve (FFR; FFRCT), transluminal attenuation gradient (TAG; TAG320), and CT coronary angiography alone to diagnose hemodynamically significant stenosis as determined by invasive FFR. MATERIALS AND METHODS: This substudy of the prospective NXT study (no. NCT01757678) was approved by each participating institution's review board, and informed consent was obtained from all participants. Fifty-one consecutive patients who underwent 320-detector row CT coronary angiographic examination and invasive coronary angiography with FFR measurement were included. Independent core laboratories determined coronary artery disease severity by using CT coronary angiography, TAG320, FFRCT, and FFR. TAG320 is defined as the linear regression coefficient between luminal attenuation and axial distance from the coronary ostium. FFRCT was computed from CT coronary angiography data by using computational fluid dynamics technology. Diagnostic performance was evaluated and compared on a per-vessel basis by the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: Among 82 vessels, 24 lesions (29%) had ischemia by FFR (FFR ≤ 0.80). FFRCT exhibited a stronger correlation with invasive FFR compared with TAG320 (Spearman ρ, 0.78 vs 0.47, respectively). Overall per-vessel accuracy, sensitivity, specificity, and positive and negative predictive values for TAG320 (<15.37) were 78%, 58%, 86%, 64%, and 83%, respectively; and those of FFRCT were 83%, 92%, 79%, 65%, and 96%, respectively. ROC curve analysis showed a significantly larger AUC for FFRCT (0.93) compared with that for TAG320 (0.72; P = .003) and CT coronary angiography alone (0.68; P = .008). CONCLUSION: FFRCT computed from 320-detector row CT coronary angiography provides better diagnostic performance for the diagnosis of hemodynamically significant coronary stenoses compared with CT coronary angiography and TAG320.

Chronic Total Occlusion - Percutaneous Coronary Intervention (CTO-PCI) Experience in a Single, Multi-operator Australian Centre: Need for dedicated CTO-PCI programs.

BACKGROUND: Chronic total occlusions (CTOs) represent a unique set of lesions for percutaneous coronary intervention (PCI) because of the complexity of techniques required to treat them. METHODS: We retrospectively reviewed the CTO-PCI experience between January 2010 and December 2012, in a multi-operator single centre, which is one of the largest volume PCI centres in Australia. RESULTS: Eighty-two patients (62.6±11.3 years, 85% males) who had CTO-PCIs were included. The most common site of CTO was the right coronary artery (44%), followed by the left circumflex (30%) and left anterior descending (26%) arteries. Using the Japanese CTO scoring system, 34% of lesions were classified as easy, 37% intermediate, 23% difficult and 6% very difficult. All PCIs were performed by antegrade approach. Selected procedural characteristics included: re-attempt procedure 10%; multiple access sites 21%; more than one guidewire 77%; additional support modality 60%; drug-eluting stents 97%; stent number 1.6±0.8; total stent length 40.1±24.5mm; fluoroscopy time 33±17min; contrast volume 257.2±110.8mL. Overall CTO success rate was 60%. In-hospital adverse outcomes included 1.2% mortality, 9.8% peri-procedural myocardial infarction, 4.9% emergency bypass surgery, 3% cardiac tamponade and 4.9% contrast induced nephropathy. CONCLUSION: We report modest success rates in a single Australian centre experience in a relatively conservative cohort of CTO-PCI prior to the initiation of a dedicated CTO revascularisation program.

The ASLA Score: A CT Angiographic Index to Predict Functionally Significant Coronary Stenoses in Lesions with Intermediate Severity-Diagnostic Accuracy.

PURPOSE: To identify computed tomographic (CT) coronary indexes independently associated with a fractional flow reserve (FFR) of 0.8 or less, to derive a score that combines CT indexes most predictive of an FFR of 0.8 or less, and to evaluate the diagnostic accuracy of the score in predicting an FFR of 0.8 or less. MATERIALS AND METHODS: This retrospective study had institutional review board approval and waiver of the need to obtain informed consent. Consecutive patients who underwent CT coronary angiography and FFR assessment with one or more discrete lesion(s) of intermediate (30%-70%) severity at CT were included. Quantitative CT measurements were performed by using dedicated software. The CT indexes evaluated included the following: plaque burden, minimal luminal area and diameter, stenosis diameter, area of stenosis, lesion length, remodeling index, plaque morphology, calcification severity, and the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) score, which approximates the size of the myocardium subtended by a lesion. By using covariates independently associated with an FFR of 0.8 or less, a score was determined on the basis of modified Akaike information criteria, and the C statistics of individual and combined indexes were compared. RESULTS: Eighty-five patients (mean age, 64.2 years; range, 48-88 years; 65.9% men; 124 lesions; 38 lesions with an FFR ≤ 0.8) were included. Area of stenosis, lesion length, and APPROACH score were the strongest predictors of an FFR of 0.8 or less and were used to derive the ASLA score. The optimism-adjusted Harrell C statistic for the combined score was 0.82, which was superior to that for area of stenosis (0.74), lesion length (0.75), and the APPROACH score (0.71) (P < .001 for trend). The corresponding incremental discrimination improvement indexes were 0.17, 0.11, and 0.19, respectively (P < .001 for all), suggesting that the score improves reclassification compared with any one angiographic index. The average time required for score derivation was 102.6 seconds. CONCLUSION: The ASLA score, which accounts for CT-derived area of stenosis, lesion length, and APPROACH score, may conveniently improve the prediction, beyond individual indexes, of functionally significant intermediate coronary lesions.

A novel coronary angiography index (DILEMMA score) for prediction of functionally significant coronary artery stenoses assessed by fractional flow reserve: A novel coronary angiography index.

BACKGROUND: Angiographic evaluation of diameter stenosis has modest predictive value for functionally significant coronary artery stenoses as assessed by fractional flow reserve (FFR). Lesion length and assessment of area of myocardium at risk (Bypass Angioplasty Revascularization Investigation [BARI] Myocardial Jeopardy Index [MJI]) subtended by the stenotic coronary arteries are also predictors of functionally significant coronary artery stenoses. We sort to assess the diagnostic accuracy of DILEMMA score, which combines minimal lumen diameter (MLD), lesion length, and BARI MJI in prediction of significantly reduced FFR (≤0.8). METHODS: We assessed patients who underwent coronary angiography and FFR. Lesion length and MLD were assessed by quantitative coronary angiography. Estimation of area of myocardium at risk subtended by coronary stenoses was performed using the BARI MJI. RESULTS: A total of 296 patients (age 64 ± 10.6 years, 68% male, 497 vessels) were included. DILEMMA score was significantly higher in vessels with significant FFR, 6.09 ± 3.23 versus 3.84 ± 2.99 (P < .001). In the derivation cohort, the optimism-adjusted Harrell c statistic for DILEMMA score was 0.82 compared with 0.76 for BARI MJI, 0.75 for lesion length, and 0.7 for MLD. In the validation cohort, the c-statistic for DILEMMA score, BARI MJI, lesion length, and MLD was 0.88, 0.77, 0.81, and 0.72, respectively. The DILEMMA score was a better predictor of FFR ≤0.8 compared with MLD, lesion length, and BARI MJI individually (P < .001, P < .02, and P < .045, respectively) on Bonferroni-adjusted pairwise comparison. CONCLUSIONS: DILEMMA score, taking into account MLD, lesion length, and BARI MJI, may have incremental predictive value beyond the individual indices alone for detecting functionally significant coronary artery stenoses.

Incremental benefits of repeated mesenchymal stromal cell administration compared with solitary intervention after myocardial infarction.

BACKGROUND AIMS: Traditionally, stem cell therapy for myocardial infarction (MI) has been administered as a single treatment in the acute or subacute period after MI. These time intervals coincide with marked differences in the post-infarct myocardial environment, raising the prospect that repeat cell dosing could provide incremental benefit beyond a solitary intervention. This prospect was evaluated with the use of mesenchymal stromal cells (MSCs). METHODS: Three groups of rats were studied. Single-therapy and dual-therapy groups received allogeneic, prospectively isolated MSCs (1 × 10(6) cells) by trans-epicardial injection immediately after MI, with additional dosing 1 week later in the dual-therapy cohort. Control animals received cryopreservant solution only. Left ventricular (LV) dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance immediately before MI and at 1, 2 and 4 weeks after MI. RESULTS: Immediate MSC treatment attenuated early myocardial damage with EF of 35.3 ± 3.1% (dual group, n = 12) and 35.2 ± 2.2% (single group, n = 15) at 1 week after MI compared with 22.1 ± 1.9% in controls (n = 17, P < 0.01). In animals receiving a second dose of MSCs, EF increased to 40.7 ± 3.1% by week 4, which was significantly higher than in the single-therapy group (EF 35.9 ± 1.8%, P < 0.05). Dual MSC treatment was also associated with greater myocardial mass and arteriolar density, with trends toward reduced myocardial fibrosis. These incremental benefits were especially observed in remote (non-infarct) segments of LV myocardium. CONCLUSIONS: Repeated stem cell intervention in both the acute and the sub-acute period after MI provides additional improvement in ventricular function beyond solitary cell dosing, largely owing to beneficial changes remote to the area of infarction.

320-row CT coronary angiography predicts freedom from revascularisation and acts as a gatekeeper to defer invasive angiography in stable coronary artery disease: a fractional flow reserve-correlated study.

OBJECTIVES: To determine the accuracy of 320-row multidetector coronary computed tomography angiography (M320-CCTA) to detect functional stenoses using fractional flow reserve (FFR) as the reference standard and to predict revascularisation in stable coronary artery disease. METHODS: One hundred and fifteen patients (230 vessels) underwent M320-CCTA and FFR assessment and were followed for 18 months. Diameter stenosis on invasive angiography (ICA) and M320-CCTA were assessed by consensus by two observers and significant stenosis was defined as ≥50%. FFR ≤0.8 indicated functionally significant stenoses. RESULTS: M320-CCTA had 94% sensitivity and 94% negative predictive value (NPV) for FFR ≤0.8. Overall accuracy was 70%, specificity 54% and positive predictive value 65%. On receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) for CCTA to predict FFR ≤0.8 was 0.74 which was comparable with ICA. The absence of a significant stenosis on M320-CCTA was associated with a 6% revascularisation rate. M320-CCTA predicted revascularisation with an AUC of 0.71 which was comparable with ICA. CONCLUSIONS: M320-CCTA has excellent sensitivity and NPV for functional stenoses and therefore may act as an effective gatekeeper to defer ICA and revascularisation. Like ICA, M320-CCTA lacks specificity for functional stenoses and only has moderate accuracy to predict the need for revascularisation. KEY POINTS: • Important information about the heart is provided by 320-row multidetector CT coronary angiography (M320-CCTA). • M320-CCTA accurately detects and excludes functional stenoses determined by fractional flow reserve (FFR). • Non-significant stenoses on M320-CCTA associated with fewer cardiac events and less revascularisation. • M320-CCTA may act as a gatekeeper for invasive angiography and inappropriate revascularisation. • Like ICA, M320-CCTA only has moderate accuracy to predict vessels requiring revascularisation.

Magnetic resonance-derived circumferential strain provides a superior and incremental assessment of improvement in contractile function in patients early after ST-segment elevation myocardial infarction.

BACKGROUND: We evaluate whether circumferential strain derived from grid-tagged CMR is a better method for assessing improvement in segmental contractile function after STEMI compared to late gadolinium enhancement (LGE). METHODS: STEMI patients post primary PCI underwent baseline CMR (day 3) and follow-up (day 90). Cine, grid-tagged and LGE images were acquired. Baseline LGE infarct hyperenhancement was categorised as ≤25 %, 26-50 %, 51-75 % and >75 % hyperenhancement. The segmental baseline circumferential strain (CS) and circumferential strain rate (CSR) were calculated from grid-tagged images. Segments demonstrating an improvement in wall motion of ≥1 grade compared to baseline were regarded as having improved segmental contractile-function. RESULTS: Forty-five patients (aged 58 ± 12 years) and 179 infarct segments were analysed. A baseline CS cutoff of -5 % had sensitivity of 89 % and specificity of 70 % for detection of improvement in segmental-contractile-function. On receiver-operating characteristic analysis for predicting improvement in contractile function, AUC for baseline CS (0.82) compared favourably to LGE hyperenhancement (0.68), MVO (0.67) and baseline-CSR (0.74). On comparison of AUCs, baseline CS was superior to LGE hyperenhancement and MVO in predicting improvement in contractile function (P < 0.001). On multivariate-analysis, baseline CS was the independent predictor of improvement in segmental contractile function (P < 0.001). CONCLUSION: Grid-tagged CMR-derived baseline CS is a superior predictor of improvement in segmental contractile function, providing incremental value when added to LGE hyperenhancement and MVO following STEMI. KEY POINTS: Baseline CS predicts contractile function recovery better than LGE and MVO following STEMI. Baseline CS predicts contractile function recovery better than baseline CSR following STEMI. Baseline CS provides incremental value to LGE and MVO following STEMI.

Beneficial cardiovascular remodeling following arterio-venous fistula ligation post-renal transplantation: a longitudinal magnetic resonance imaging study.

Despite improvements in survival following renal transplantation, high rates of cardiovascular morbidity and mortality remain. Persistence of arterio-venous fistulae (AVF) may contribute to maladaptive cardiovascular remodeling and poor health outcomes in this cohort. Utilizing recent advances in cardiovascular magnetic resonance imaging (CMR), we prospectively evaluated alterations in cardiac and vascular structure and function six months after elective ligation of AVF, following stable, successful renal transplantation. Eighteen subjects underwent CMR evaluation of cardiac structure and function, aortic distensibility and endothelial function prior to AVF ligation and at six months. At follow-up, while left ventricular ejection fraction was unchanged, mean cardiac output decreased by 15.6% (9.6 ± 2.9 L/min vs. 8.1 ± 2.3 L/min, p = 0.004) and left ventricular mass had regressed by 10% (166 ± 56 g vs. 149 ± 51 g, p = 0.0001). Significant improvements were also noted in right ventricular and biatrial structure and function. Aortic distensibility was unchanged at follow-up, but endothelial dependent vasodilatation had improved (2.5 ± 6.5% vs. 8.0 ± 5.9%, p = 0.04). Elective AVF ligation following successful renal transplantation is associated with improvements in left ventricular mass, right ventricular, and biatrial structure and function. Further randomized studies are warranted to determine the potential clinical improvement following AVF ligation in this cohort.

An update on stem cell therapies for acute coronary syndrome.

Well into the second decade since its conception, cell transplantation continues to undergo intensive evaluation for the treatment of myocardial infarction. At a mechanistic level, its objectives remain to replace lost cardiac cell mass with new functioning cardiomyocytes and vascular cells, thereby minimizing infarct size and scar formation, and improving clinical outcomes by preventing adverse left ventricular remodeling and recurrent ischemic events. Many different cell types, including pluripotent stem cells and various adult-derived progenitor cells, have been shown to have therapeutic potential in preclinical studies, while early phase human trial experience has provided divergent outcomes and fundamental lessons, emphasizing that there remain key issues to address and challenges to overcome before cell therapy can be applied to wider clinical practice. The purpose of this review is to provide a balanced update on recent seminal developments in this exciting field and look to the next important steps to ensure its forward progression.

Protocol and rationale of the Australian multicentre registry for serial cardiac computed tomography angiography (ARISTOCRAT): a prospective observational study of the natural history of pericoronary adipose tissue attenuation and radiomics.

Background: Vascular inflammation plays a crucial role in the development of atherosclerosis and atherosclerotic plaque rupture resulting in acute coronary syndrome (ACS). Pericoronary adipose tissue (PCAT) attenuation quantified from routine coronary computed tomography angiography (CCTA) has emerged as a promising non-invasive imaging biomarker of coronary inflammation. However, a detailed understanding of the natural history of PCAT attenuation is required before it can be used as a surrogate endpoint in trials of novel therapies targeting coronary inflammation. This article aims to explore the natural history of PCAT attenuation and its association with changes in plaque characteristics. Methods: The Australian natuRal hISTOry of periCoronary adipose tissue attenuation, RAdiomics and plaque by computed Tomographic angiography (ARISTOCRAT) registry is a multi-centre observational registry enrolling patients undergoing clinically indicated serial CCTA in 9 centres across Australia. CCTA scan parameters will be matched across serial scans. Quantitative analysis of plaque and PCAT will be performed using semiautomated software. Discussion: The primary endpoint is to explore temporal changes in patient-level and lesion-level PCAT attenuation by CCTA and their associations with changes in plaque characteristics. Secondary endpoints include evaluating: (I) impact of statin therapy on PCAT attenuation and plaque characteristics; and (II) changes in PCAT attenuation and plaque characteristics in specific subgroups according to sex and risk factors. ARISTOCRAT will further our understanding of the natural history of PCAT attenuation and its association with changes in plaque characteristics. Trial Registration: This study has been prospectively registered with the Australia and New Zealand Clinical Trials Registry (ACTRN12621001018808).

Tandem lesions associate with angiographic progression of coronary artery stenoses.

Background: Although the clinical factors associated with progression of coronary artery disease have been well studied, the angiographic predictors are less defined. Objectives: Our objective was to study the clinical and angiographic factors that associate with progression of coronary artery stenoses. Methods: We conducted a retrospective analysis of consecutive patients undergoing multiple, clinically indicated invasive coronary angiograms with an interval greater than 6 months, between January 2013 and December 2016. Lesion segments were analysed using Quantitative Coronary Angiography (QCA) if a stenosis ≥ 20 % was identified on either angiogram. Stenosis progression was defined as an increase ≥ 10 % in stenosis severity, with progressor groups analysed on both patient and lesion levels. Mixed-effects regression analyses were performed to evaluate factors associated with progression of individual stenoses. Results: 199 patients were included with 881 lesions analysed. 108 (54.3 %) patients and 186 (21.1 %) stenoses were classified as progressors. The median age was 65 years (IQR 56-73) and the median interval between angiograms was 2.1 years (IQR 1.2-3.0). On a patient level, age, number of lesions and presence of multivessel disease at baseline were each associated with progressor status. On a lesion level, presence of a stenosis downstream (OR 3.07, 95 % CI 2.04-4.63, p < 0.001) and circumflex artery stenosis location (OR 1.81, 95 % CI 1.21-2.7, p = 0.004) were associated with progressor status. Other lesion characteristics did not significantly impact progressor status or change in stenosis severity. Conclusion: Coronary lesions which have a downstream stenosis may be at increased risk of stenosis progression. Further research into the mechanistic basis of this finding is required, along with its implications for plaque vulnerability and clinical outcomes.

Impact of timing and dose of mesenchymal stromal cell therapy in a preclinical model of acute myocardial infarction.

BACKGROUND: Although mesenchymal stem/stromal cells (MSC) have shown therapeutic promise after myocardial infarction (MI), the impact of cell dose and timing of intervention remains uncertain. We compared immediate and deferred administration of 2 doses of MSC in a rat model of MI. METHODS AND RESULTS: Sprague-Dawley rats were used. Allogeneic prospectively isolated MSC ("low" dose 1 × 10(6) or "high" dose 2 × 10(6) cells) were delivered by transepicardial injection immediately after MI ("early-low," "early-high"), or 1 week later ("late-low," "late-high"). Control subjects received cryopreservant solution alone. Left ventricular dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance. All 4 MSC-treatment cohorts demonstrated higher EF than control animals 4 weeks after MI (P values <.01 to <.0001), with function most preserved in the early-high group (absolute reduction in EF from baseline: control 39.1 ± 1.7%, early-low 26.5 ± 3.2%, early-high 7.9 ± 2.6%, late-low 19.6 ± 3.5%, late-high 17.9 ± 4.0%). Cell treatment also attenuated left ventricular dilatation and fibrosis and augmented left ventricular mass, systolic wall thickening (SWT), and microvascular density. Although early intervention selectively increased SWT and vascular density in the infarct territory, delayed treatment caused greater benefit in remote (noninfarct) myocardium. All outcomes demonstrated dose dependence for early MSC treatment, but not for later cell administration. CONCLUSIONS: The nature and magnitude of benefit from MSC after acute MI is strongly influenced by timing of cell delivery, with dose dependence most evident for early intervention. These novel insights have potential implications for cell therapy after MI in human patients.