Patrick A. Calvert

18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial.

BACKGROUND The use of non-invasive imaging to identify ruptured or high-risk coronary atherosclerotic plaques would represent a major clinical advance for prevention and treatment of coronary artery disease. We used combined PET and CT to identify ruptured and high-risk atherosclerotic plaques using the radioactive tracers (18)F-sodium fluoride ((18)F-NaF) and (18)F-fluorodeoxyglucose ((18)F-FDG). METHODS In this prospective clinical trial, patients with myocardial infarction (n=40) and stable angina (n=40) underwent (18)F-NaF and (18)F-FDG PET-CT, and invasive coronary angiography. (18)F-NaF uptake was compared with histology in carotid endarterectomy specimens from patients with symptomatic carotid disease, and with intravascular ultrasound in patients with stable angina. The primary endpoint was the comparison of (18)F-fluoride tissue-to-background ratios of culprit and non-culprit coronary plaques of patients with acute myocardial infarction. FINDINGS In 37 (93%) patients with myocardial infarction, the highest coronary (18)F-NaF uptake was seen in the culprit plaque (median maximum tissue-to-background ratio: culprit 1·66 [IQR 1·40-2·25] vs highest non-culprit 1·24 [1·06-1·38], p<0·0001). By contrast, coronary (18)F-FDG uptake was commonly obscured by myocardial uptake and where discernible, there were no differences between culprit and non-culprit plaques (1·71 [1·40-2·13] vs 1·58 [1·28-2·01], p=0·34). Marked (18)F-NaF uptake occurred at the site of all carotid plaque ruptures and was associated with histological evidence of active calcification, macrophage infiltration, apoptosis, and necrosis. 18 (45%) patients with stable angina had plaques with focal (18)F-NaF uptake (maximum tissue-to-background ratio 1·90 [IQR 1·61-2·17]) that were associated with more high-risk features on intravascular ultrasound than those without uptake: positive remodelling (remodelling index 1·12 [1·09-1·19] vs 1·01 [0·94-1·06]; p=0·0004), microcalcification (73% vs 21%, p=0·002), and necrotic core (25% [21-29] vs 18% [14-22], p=0·001). INTERPRETATION (18)F-NaF PET-CT is the first non-invasive imaging method to identify and localise ruptured and high-risk coronary plaque. Future studies are needed to establish whether this method can improve the management and treatment of patients with coronary artery disease. FUNDING Chief Scientist Office Scotland and British Heart Foundation.

Association Between IVUS Findings and Adverse Outcomes in Patients With Coronary Artery Disease The VIVA (VH-IVUS in Vulnerable Atherosclerosis) Study

OBJECTIVES The purpose of this study was to determine whether thin-capped fibroatheromata (TCFA) identified by virtual histology intravascular ultrasound (VH-IVUS) are associated with major adverse cardiac events (MACE) on individual plaque or whole patient analysis. BACKGROUND Post-mortem studies have identified TCFA as the substrate for most myocardial infarctions. However, little is known about the natural history of individual TCFA and their link with MACE. VH-IVUS provides a method of identifying plaques in vivo that are similar (although not identical) to histologically defined TCFA, and has been validated in human atherectomy and post-mortem studies. METHODS One hundred seventy patients with stable angina or troponin-positive acute coronary syndrome referred for percutaneous coronary intervention (PCI) were prospectively enrolled and underwent 3-vessel VH-IVUS pre-PCI and also post-PCI in the culprit vessel. MACE consisted of death, myocardial infarction, or unplanned revascularization. RESULTS In all, 30,372 mm of VH-IVUS were analyzed. Eighteen MACE occurred in 16 patients over a median follow-up of 625 days (interquartile range: 463 to 990 days); 1,096 plaques were classified, and 19 lesions resulted in MACE (13 nonculprit lesions and 6 culprit lesions). Nonculprit lesion factors associated with nonrestenotic MACE included VHTCFA (hazard ratio [HR]: 7.53, p = 0.038) and plaque burden >70% (HR: 8.13, p = 0.011). VHTCFA (HR: 8.16, p = 0.007), plaque burden >70% (HR: 7.48, p < 0.001), and minimum luminal area <4 mm(2) (HR: 2.91, p = 0.036) were associated with total MACE. On patient-based analysis, the only factor associated with nonrestenotic MACE was 3-vessel noncalcified VHTCFA (HR: 1.79, p = 0.004). CONCLUSIONS VH-IVUS TCFA was associated with nonrestenotic and total MACE on individual plaque analysis, and noncalcified VHTCFA was associated with nonrestenotic and total MACE on whole-patient analysis, demonstrating that VH-IVUS can identify plaques at increased risk of subsequent events. The preservation of the association between VHTCFA and MACE despite various analyses emphasizes its biological importance.

Mitochondrial DNA Damage Can Promote Atherosclerosis Independently of Reactive Oxygen Species Through Effects on Smooth Muscle Cells and Monocytes and Correlates With Higher-Risk Plaques in Humans

Background— Mitochondrial DNA (mtDNA) damage occurs in both circulating cells and the vessel wall in human atherosclerosis. However, it is unclear whether mtDNA damage directly promotes atherogenesis or is a consequence of tissue damage, which cell types are involved, and whether its effects are mediated only through reactive oxygen species. Methods and Results— mtDNA damage occurred early in the vessel wall in apolipoprotein E–null (ApoE−/−) mice, before significant atherosclerosis developed. mtDNA defects were also identified in circulating monocytes and liver and were associated with mitochondrial dysfunction. To determine whether mtDNA damage directly promotes atherosclerosis, we studied ApoE−/− mice deficient for mitochondrial polymerase-&ggr; proofreading activity (polG−/−/ApoE−/−). polG−/−/ApoE−/− mice showed extensive mtDNA damage and defects in oxidative phosphorylation but no increase in reactive oxygen species. polG−/−/ApoE−/− mice showed increased atherosclerosis, associated with impaired proliferation and apoptosis of vascular smooth muscle cells, and hyperlipidemia. Transplantation with polG−/−/ApoE−/− bone marrow increased the features of plaque vulnerability, and polG−/−/ApoE−/− monocytes showed increased apoptosis and inflammatory cytokine release. To examine mtDNA damage in human atherosclerosis, we assessed mtDNA adducts in plaques and in leukocytes from patients who had undergone virtual histology intravascular ultrasound characterization of coronary plaques. Human atherosclerotic plaques showed increased mtDNA damage compared with normal vessels; in contrast, leukocyte mtDNA damage was associated with higher-risk plaques but not plaque burden. Conclusions— We show that mtDNA damage in vessel wall and circulating cells is widespread and causative and indicates higher risk in atherosclerosis. Protection against mtDNA damage and improvement of mitochondrial function are potential areas for new therapeutics.

Patent foramen ovale: anatomy, outcomes, and closure.

Patent foramen ovale (PFO) is a normal fetal communication between the right and left atria that persists after birth. PFO is a common finding that occurs in 20–34% of the population, although its prevalence decreases with age. In most cases, a PFO poses no threat to health. However, some PFOs have the ability to open widely under certain hemodynamic conditions, which enables any bloodborne material, such as thrombi, air, or vasoactive substances, to pass from the venous to the arterial circulation, with the potential to cause a cerebrovascular event. PFO has been linked to several conditions, including cryptogenic stroke, migraine with aura, decompression illness, and systemic arterial embolism. However, the data that support PFO closure in these conditions are mostly from nonrandomized cohort series, and are often contradictory. In this Review, we discuss the existing data on PFO closure, including results of the first randomized, controlled trial comparing device closure of PFO with medical therapy for cryptogenic stroke, and we examine controversies in the literature as well as ongoing studies. We also focus on the anatomy of a PFO and how it impacts on the procedure of PFO closure with a percutaneous device.

Atherosclerotic plaque composition and classification identified by coronary computed tomography: assessment of computed tomography-generated plaque maps compared with virtual histology intravascular ultrasound and histology.

Background— Computed tomography (CT) is used routinely for coronary angiography, and higher-risk features of plaques can also be identified. However, the ability of CT to discriminate individual plaque components and classify plaques according to accepted histological definitions is unknown. Methods and Results— We first determined CT attenuation ranges for individual plaque components using combined in vivo CT coregistered with virtual histology intravascular ultrasound (VH-IVUS) in 108 plaques from 57 patients. Comparison with contrast attenuation created plaque/contrast attenuation ratios that were significantly different for each component. In a separate validation cohort of 47 patients, these Plaque Maps correlated significantly with VH-IVUS–determined plaque component volumes (necrotic core: r=0.41, P=0.002; fibrous plaque: r=0.54, P<0.001; calcified plaque: r=0.59, P<0.001; total plaque: r=0.62, P<0.001). We also assessed VH-IVUS and CT Plaque Maps against coregistered histology in 72 (VH-IVUS) and 87 (CT) segments from 8 postmortem coronary arteries. The diagnostic accuracy of CT to detect calcified plaque (83% versus 92%), necrotic core (80% versus 65%), and fibroatheroma (80% versus 79%) was comparable with VH-IVUS. However, although VH-IVUS could identify thin-cap fibroatheromas (TCFA) with a diagnostic accuracy of between 74% and 82% (depending on the TCFA definition used), the spatial resolution of CT prevented direct identification of TCFA. Conclusions— CT-derived Plaque Maps based on contrast-adjusted attenuation ranges can define individual plaque components with a similar accuracy to VH-IVUS ex vivo. However, coronary CT Plaque Maps could not reliably classify plaques and identify TCFA, such that high-risk plaques may be misclassified or overlooked.

Coronary Plaque Structural Stress Is Associated With Plaque Composition and Subtype and Higher in Acute Coronary Syndrome The BEACON I (Biomechanical Evaluation of Atheromatous Coronary Arteries) Study

Background—Atherosclerotic plaques underlying most myocardial infarctions have thin fibrous caps and large necrotic cores; however, these features alone do not reliably identify plaques that rupture. Rupture occurs when plaque structural stress (PSS) exceeds mechanical strength. We examined whether PSS could be calculated in vivo based on virtual histology (VH) intravascular ultrasound and whether PSS varied according to plaque composition, subtype, or clinical presentation. Methods and Results—A total of 4429 VH intravascular ultrasound frames from 53 patients were analyzed, identifying 99 584 individual plaque components. PSS was calculated by finite element analysis in whole vessels, in individual plaques, and in higher-risk regions (plaque burden ≥70%, mean luminal area ⩽4 mm2, noncalcified VH-defined thin-cap fibroatheroma). Plaque components including total area/arc of calcification (R2=0.33; P<0.001 and R2=0.28; P<0.001) and necrotic core (R2=0.18; P<0.001 and R2=0.15; P<0.001) showed complex, nonlinear relationships with PSS. PSS was higher in noncalcified VH-defined thin-cap fibroatheroma compared with thick-cap fibroatheromas (median [Q1–Q3], 8.44 [6.97–10.64] versus 7.63 [6.37–9.68]; P=0.002). PSS was also higher in patients with an acute coronary syndrome, where mean luminal area ⩽4 mm2 (8.24 [7.06–9.93] versus 7.72 [6.33–9.34]; P=0.03), plaque burden ≥70% (9.18 [7.44–10.88] versus 7.93 [6.16–9.46]; P=0.02), and in noncalcified VH-defined thin-cap fibroatheroma (9.23 [7.33–11.44] versus 7.65 [6.45–8.62]; P=0.02). Finally, PSS increased the positive predictive value for VH intravascular ultrasound to identify clinical presentation. Conclusions—Finite element analysis modeling demonstrates that structural stress is highly variable within plaques, with increased PSS associated with plaque composition, subtype, and higher-risk regions in patients with acute coronary syndrome. PSS may represent a novel tool to analyze the dynamic behavior of coronary plaques with the potential to improve prediction of plaque rupture.

Leukocyte Telomere Length Is Associated With High-Risk Plaques on Virtual Histology Intravascular Ultrasound and Increased Proinflammatory Activity

Objective— Leukocyte telomere length (LTL), a marker of cellular senescence, is inversely associated with cardiovascular events. However, whether LTL reflects plaque extent or unstable plaques, and the mechanisms underlying any association are unknown. Methods and Results— One hundred seventy patients with stable angina or acute coronary syndrome referred for percutaneous coronary intervention underwent 3-vessel virtual histology intravascular ultrasound; 30 372 mm of intravascular ultrasound pullback and 1096 plaques were analyzed. LTL was not associated with plaque volume but was associated with calcified thin-capped fibroatheroma (OR, 1.24; CI, 1.01–1.53; P=0.039) and total fibroatheroma numbers (OR, 1.19; CI, 1.02–1.39; P=0.027). Monocytes from coronary artery disease patients showed increased secretion of proinflammatory cytokines. To mimic leukocyte senescence, we disrupted telomeres and binding and expression of the telomeric protein protection of telomeres protein-1, inducing DNA damage. Telomere disruption increased monocyte secretion of monocyte chemoattractant protein-1, IL-6, and IL-1&bgr; and oxidative burst, similar to that seen in coronary artery disease patients, and lymphocyte secretion of IL-2 and reduced lymphocyte IL-10. Conclusion— Shorter LTL is associated with high-risk plaque morphology on virtual histology intravascular ultrasound but not total 3-vessel plaque burden. Monocytes with disrupted telomeres show increased proinflammatory activity, which is also seen in coronary artery disease patients, suggesting that telomere shortening promotes high-risk plaque subtypes by increasing proinflammatory activity.

Dual-energy computed tomography imaging to determine atherosclerotic plaque composition: A prospective study with tissue validation

Background Identifying vulnerable coronary plaque with coronary CT angiography is limited by overlap between attenuation of necrotic core and fibrous plaque. Using x-rays with differing energies alters attenuation values of these components, depending on their material composition. Objectives We sought to determine whether dual-energy CT (DECT) improves plaque component discrimination compared with single-energy CT (SECT). Methods Twenty patients underwent DECT and virtual histology intravascular ultrasound (VH-IVUS). Attenuation changes at 100 and 140 kV for each plaque component were defined, using 1088 plaque areas co-registered with VH-IVUS. Hounsfield unit thresholds that best detected necrotic core were derived for SECT (conventional attenuation values) and for DECT (using dual-energy indices, defined as difference in Hounsfield unit values at the 2 voltages/their sum). Sensitivity of SECT and DECT to detect plaque components was determined in 77 segments from 7 postmortem coronary arteries. Finally, we examined 60 plaques in vivo to determine feasibility and sensitivity of clinical DECT to detect VH-IVUS–defined necrotic core. Results In contrast to conventional SECT, mean dual-energy indices of necrotic core and fibrous tissue were significantly different with minimal overlap of ranges (necrotic core, 0.007 [95% CI, –0.001 to 0.016]; fibrous tissue, 0.028 [95% CI, 0.016–0.050]; P < .0001). DECT increased diagnostic accuracy to detect necrotic core in postmortem arteries (sensitivity, 64%; specificity, 98%) compared with SECT (sensitivity, 50%; specificity, 94%). DECT sensitivity to detect necrotic core was lower when analyzed in vivo, although still better than SECT (45% vs 39%). Conclusions DECT improves the differentiation of necrotic core and fibrous plaque in ex vivo postmortem arteries. However, much of this improvement is lost when translated to in vivo imaging because of a reduction in image quality.

Direct Comparison of Virtual-Histology Intravascular Ultrasound and Optical Coherence Tomography Imaging for Identification of Thin-Cap Fibroatheroma

Background—Although rupture of thin-cap fibroatheroma (TCFA) underlies most myocardial infarctions, reliable TCFA identification remains challenging. Virtual-histology intravascular ultrasound (VH-IVUS) and optical coherence tomography (OCT) can assess tissue composition and classify plaques. However, direct comparisons between VH-IVUS and OCT are lacking and it remains unknown whether combining these modalities improves TCFA identification. Methods and Results—Two hundred fifty-eight regions-of-interest were obtained from autopsied human hearts, with plaque composition and classification assessed by histology and compared with coregistered ex vivo VH-IVUS and OCT. Sixty-seven regions-of-interest were classified as fibroatheroma on histology, with 22 meeting criteria for TCFA. On VH-IVUS, plaque (10.91±4.82 versus 8.42±4.57 mm2; P=0.01) and necrotic core areas (1.59±0.99 versus 1.03±0.85 mm2; P=0.02) were increased in TCFA versus other fibroatheroma. On OCT, although minimal fibrous cap thickness was similar (71.8±44.1 &mgr;m versus 72.6±32.4; P=0.30), the number of continuous frames with fibrous cap thickness ⩽85 &mgr;m was higher in TCFA (6.5 [1.75–11.0] versus 2.0 [0.0–7.0]; P=0.03). Maximum lipid arc on OCT was an excellent discriminator of fibroatheroma (area under the curve, 0.92; 95% confidence interval, 0.87–0.97) and TCFA (area under the curve, 0.86; 95% confidence interval, 0.81–0.92), with lipid arc ≥80° the optimal cut-off value. Using existing criteria, the sensitivity, specificity, and diagnostic accuracy for TCFA identification was 63.6%, 78.1%, and 76.5% for VH-IVUS and 72.7%, 79.8%, and 79.0% for OCT. Combining VH-defined fibroatheroma and fibrous cap thickness ⩽85 &mgr;m over 3 continuous frames improved TCFA identification, with diagnostic accuracy of 89.0%. Conclusions—Both VH-IVUS and OCT can reliably identify TCFA, although OCT accuracy may be improved using lipid arc ≥80° and fibrous cap thickness ⩽85 &mgr;m over 3 continuous frames. Combined VH-IVUS/OCT imaging markedly improved TCFA identification.

Transfemoral implantation of an Edwards SAPIEN valve in a tricuspid bioprosthesis without fluoroscopic landmarks.

AIMS We describe the first report of an Edwards SAPIEN valve implanted in a tricuspid bioprosthesis from the femoral vein. We highlight the feasibility of this previously avoided approach and the techniques involved. METHODS AND RESULTS A 61-year-old woman with multiple valve replacements for rheumatic heart disease presented with NHYA IV dyspnoea secondary to a severely stenosed tricuspid bioprosthesis. After failed aggressive medical therapy and surgical turn down, an Edwards SAPIEN XT valve was deployed in the tricuspid bioprosthesis via the right femoral vein. Adaptations to the standard transfemoral transcatheter aortic valve implantation (TAVI) technique included: (1) crossing the tricuspid bioprosthesis with a balloon floatation catheter; (2) temporary pacing wire in the coronary sinus rather than the right ventricle; (3) mounting of the SAPIEN XT valve in the reverse orientation to transfemoral TAVI; and (4) fine positioning of the final valve position pre-deployment by 3D transoesophageal echocardiography (3D TOE) alone due to complete radiolucency of the tricuspid bioprosthesis. The procedure was completed without complication and resulted in significant symptomatic improvement. CONCLUSIONS Deployment of an Edwards SAPIEN valve in a tricuspid bioprosthesis via the femoral vein is feasible and, with careful adaptations to established TAVI techniques, can be performed without complications and with good clinical response.