Alarmin-activated B cells accelerate murine atherosclerosis after myocardial infarction via plasma cell-immunoglobulin-dependent mechanisms.

AIMS: Myocardial infarction (MI) accelerates atherosclerosis and greatly increases the risk of recurrent cardiovascular events for many years, in particular, strokes and MIs. Because B cell-derived autoantibodies produced in response to MI also persist for years, we investigated the role of B cells in adaptive immune responses to MI. METHODS AND RESULTS: We used an apolipoprotein-E-deficient (ApoE-/-) mouse model of MI-accelerated atherosclerosis to assess the importance of B cells. One week after inducing MI in atherosclerotic mice, we depleted B cells using an anti-CD20 antibody. This treatment prevented subsequent immunoglobulin G accumulation in plaques and MI-induced accelerated atherosclerosis. In gain of function experiments, we purified spleen B cells from mice 1 week after inducing MI and transferred these cells into atherosclerotic ApoE-/- mice, which greatly increased immunoglobulin G (IgG) accumulation in plaque and accelerated atherosclerosis. These B cells expressed many cytokines that promote humoural immunity and in addition, they formed germinal centres within the spleen where they differentiated into antibody-producing plasma cells. Specifically deleting Blimp-1 in B cells, the transcriptional regulator that drives their terminal differentiation into antibody-producing plasma cells prevented MI-accelerated atherosclerosis. Alarmins released from infarcted hearts were responsible for activating B cells via toll-like receptors and deleting MyD88, the canonical adaptor protein for inflammatory signalling downstream of toll-like receptors, prevented B-cell activation and MI-accelerated atherosclerosis. CONCLUSION: Our data implicate early B-cell activation and autoantibodies as a central cause for accelerated atherosclerosis post-MI and identifies novel therapeutic strategies towards preventing recurrent cardiovascular events such as MI and stroke.

CT-Derived Fractional Flow Reserve (FFRCT): From Gatekeeping to Roadmapping.

Coronary computed tomography angiography (CCTA) has emerged as the preferred modality in the diagnosis of coronary artery disease, but it is limited by modest specificity. By applying principles of computational fluid dynamics, flow fraction reserve, a measure of lesion-specific ischemia that is used to guide revascularization, can be noninvasively derived from CCTA, the so-called computed tomography-derived flow fractional reserve (FFRCT). The accuracy of FFRCT in discriminating ischemia has been extensively validated, and it has been shown to improve the specificity of CCTA. Compared to other stress myocardial perfusion imaging, FFRCT has superior or comparable accuracy. Clinical studies have provided strong evidence that FFRCT has significant prognostic implications and informs clinical decisions for revascularization, serving as a gatekeeper to invasive coronary angiography. In addition, FFRCT-based tools can be used to simulate the physiological consequences of different revascularization strategies, thus providing the roadmap to achieve complete revascularization. Although challenges remain, ongoing research and randomized controlled trials are expected to address current limitations and better define its role in clinical practice.

Pulmonary Vein Isolation for Atrial Fibrillation Can Be Achieved With Low Radiation Exposure.

BACKGROUND: Atrial fibrillation is common and management by pharmacotherapy is limited by modest efficacy and significant toxicities. Pulmonary vein isolation (PVI) is a safe and effective alternative in select patients with atrial fibrillation. However, prolonged procedure time raises concerns of health risks from radiation exposure. This study aims to determine the significance of radiation exposure from PVI. METHODS: In this study, we retrospectively reviewed patient demographics, fluoroscopy time, entrance skin dose and dose area product in 80 cases of PVI, radiofrequency ablation for atrial flutter and diagnostic coronary angiogram performed in our institution. RESULTS: Compared to other procedures, patients who underwent PVI were younger (age, mean±standard error of mean, 59.4±1.1 years old, p<0.0001) and were more likely to be male (82%, p<0.001). Body mass index was similar between the three groups. The median (and interquartile range) fluoroscopy time was similar between PVI (20.8 and 13.1-30.7mins) and flutter ablation (17.6 and 11.1-26.1mins) but longer than diagnostic angiography (4.2 and 2.3-6.7mins, p<0.0001). Entrance skin dose was similar between PVI and flutter ablation groups but significantly higher in the diagnostic angiography group, with median and IQR for PVI vs. flutter ablation vs. diagnostic angiography, 100.4 (52.8-179.9) vs. 73.2 (37.0-142.1) vs. 393.5 (276.1-555.6) mGy (p<0.0001). Dose area product in PVI (1831.2 and 887.7-3460.8cGycm2) was higher than flutter ablation (1077.8 and 452.9-2410.2cGycm2, p<0.05) but lower than the diagnostic angiography group (3446.8 and 2341.9-5283.1cGycm2, p<0.0001). The fluoroscopy time and entrance skin dose for PVI decreased over time, likely due to increased operator experience. CONCLUSIONS: Despite prolonged procedure time, radiation exposure from PVI was comparable to, or lower than, other fluoroscopy-guided cardiac procedures.

Routine aspiration thrombectomy improves the diagnosis and management of embolic myocardial infarction.

OBJECTIVES: Assess the effect of aspiration thrombectomy on diagnosis and management of embolic acute myocardial infarction. BACKGROUND: Discrimination of embolic acute myocardial infarction from atherosclerotic plaque rupture/erosion prompts oral anticoagulation treatment of source of embolus, as well as avoiding unnecessary stenting and dual antiplatelet therapy. However, detection is difficult without aspiration. METHODS: We compared rates of diagnosis of embolic infarction for 2.5 years prior to (pre-RAT) and 2.5 years post routine aspiration thrombectomy (post-RAT). Baseline demographics, outcomes, and treatment strategies were also compared between the embolic infarction and atherosclerotic infarction. RESULTS: Diagnosed embolic infarction rose from 1.2% in the pre-RAT era to 2.8% in the post-RAT period (P < 0.05). In addition, more successful removal of thrombus by aspiration led to less stenting (20% vs. 55% P < 0.05) in the post-RAT period thus avoiding the hazards of "triple therapy." Embolic infarction was more frequently associated with atrial fibrillation (55% vs. 8%), had higher mortality (17% vs. 4%), and had higher rates of embolic stroke (13% vs. 0.3%) when compared with atherosclerotic MI (all P < 0.05). CONCLUSIONS: Routine aspiration thrombectomy more readily identifies embolic infarction allowing more specific therapy and avoidance of stenting and triple anticoagulant therapy.

Secondary Mitral Regurgitation: Cardiac Remodeling, Diagnosis, and Management.

Secondary mitral regurgitation (MR) refers to MR resulting from left ventricular or left atrial remodeling. In ischemic or nonischemic cardiomyopathy, left ventricular dilation (regional or global) leads to papillary muscle displacement, tethering, and leaflet malcoaptation. In atrial functional MR, MR occurs in patients with left atrial dilation and altered mitral annular geometry due to atrial fibrillation. In addition to cardiac remodeling, leaflet remodeling is increasingly recognized. Mitral leaflet tissue actively adapts through leaflet growth to ensure adequate coaptation. Leaflets, however, can also undergo maladaptive thickening and fibrosis, leading to increased stiffness. The balance of cardiac and leaflet remodeling is a key determinant in the development of secondary MR. Clinical management starts with detection, severity grading, and identification of the underlying mechanism, which relies heavily on echocardiography. Treatment of secondary MR consists of guideline-directed medical therapy, surgical repair or replacement, and transcatheter edge-to-edge repair. Based on a better understanding of pathophysiology, novel percutaneous mitral repair and replacement devices have been developed and clinical trials are underway.

A comparative assessment of the performance of a state-of-the art small footprint dedicated cardiovascular CT scanner.

INTRODUCTION: With increasing adoption of CT coronary angiography (CTA) there is increasing demand for cost-effective, small footprint, dedicated cardiac scanners. We compared a state-of-the-art, small footprint dedicated cardiac scanner (DCCT) to a standard multidetector scanner (MDCT). METHODS: The study was a retrospective unblinded single centre study. A total of 800 patients were included, with 400 undergoing a DCCT and MDCT coronary CTA scanning, respectively. Image quality was assessed using a 4-point grading score. Image noise and artifact, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), and acceptance rate for CT-derived fractional flow reserve (FFRct) were recorded. RESULTS: Overall image quality was higher in the DCCT group (3.8 ± 0.55 vs 3.6 ± 0.69; p = 0.042). There was no difference in overall image noise (p = 0.131) or artifact (p = 0.295). SNR was superior in the DCCT group (14.2 ± 6.85 vs 11.4 ± 3.32; p < 0.005) as was CNR (12.7 ± 6.77 vs 11.9 ± 3.29; p < 0.005). The heart rate was lower in the DCCT group (56 ± 9.1 vs 59 ± 8.1; p < 0.005). No difference in the dose length product (DLP median 244.53 (IQR 105.6) vs 237.63 (IQR 160.1); p = 0.313) or FFRCT acceptance rate (100 vs 97.7%; p > 0.05) was noted. Independent predictors of excellent quality regardless of scanner type were age (p = 0.011), heart rate <65 bpm (p < 0.005), and body mass index < 35 (p < 0.005). CONCLUSION: A DCCT scanner is capable of image quality similar to modern current generation general purpose CT technology. Such technology appears to be a viable option to serve the increasing demand for CTCA imaging.

Effects of chronic kidney disease and declining renal function on coronary atherosclerotic plaque progression: a PARADIGM substudy.

AIMS: To investigate the change in atherosclerotic plaque volume in patients with chronic kidney disease (CKD) and declining renal function, using coronary computed tomography angiography (CCTA). METHODS AND RESULTS: In total, 891 participants with analysable serial CCTA and available glomerular filtration rate (GFR, derived using Cockcroft-Gault formulae) at baseline (CCTA 1) and follow-up (CCTA 2) were included. CKD was defined as GFR <60 mL/min/1.73 m2. Declining renal function was defined as ≥10% drop in GFR from the baseline. Quantitative assessment of plaque volume and composition were performed on both scans. There were 203 participants with CKD and 688 without CKD. CKD was associated with higher baseline total plaque volume, but similar plaque progression, measured by crude (57.5 ± 3.4 vs. 65.9 ± 7.7 mm3/year, P = 0.28) or annualized (17.3 ± 1.0 vs. 19.9 ± 2.0 mm3/year, P = 0.25) change in total plaque volume. There were 709 participants with stable GFR and 182 with declining GFR. Declining renal function was independently associated with plaque progression, with higher crude (54.1 ± 3.2 vs. 80.2 ± 9.0 mm3/year, P < 0.01) or annualized (16.4 ± 0.9 vs. 23.9 ± 2.6 mm3/year, P < 0.01) increase in total plaque volume. In CKD, plaque progression was driven by calcified plaques whereas in patients with declining renal function, it was driven by non-calcified plaques. CONCLUSION: Decline in renal function was associated with more rapid plaque progression, whereas the presence of CKD was not.

Transcatheter Mitral Valve Repair and Replacement: Current Evidence for Intervention and the Role of CT in Preprocedural Planning-A Review for Radiologists and Cardiologists Alike.

The mitral valve is a complex structure with a three-dimensional saddle shape annulus. Mitral regurgitation occurs from leaflet coaptation failure that is either primary (a problem with the leaflets) or secondary (chamber dilatation in the setting of cardiomyopathy). There has been an increase in focus on transcatheter mitral valve interventions, for both mitral repair and replacement. These technologies have rapidly developed to provide treatment for a substantial number of patients with severe symptomatic mitral regurgitation who are at too high of a risk to undergo open heart surgery. CT assessment of the mitral valve has developed with equal rapidity, with regard to preprocedural planning for transcatheter therapies. This review will provide an overview of mitral valve anatomy, an update on the current transcatheter repair and replacement therapies, as well as a focused overview of the role of multislice CT in mitral assessment prior to intervention. © RSNA, 2020.

Evaluation of an Explanted Tiara Transcatheter Mitral Valve.

Post-explant (ex vivo) evaluation of medical devices is an essential part of quality assurance, quality improvement, and further device development. Central to this is detailed pathological analysis. Here, we provide the first such evaluation of an explanted Tiara transcatheter mitral valve prosthesis. (Level of Difficulty: Advanced.).

Physical inactivity rapidly induces insulin resistance and microvascular dysfunction in healthy volunteers.

OBJECTIVE: Sedentary lifestyle increases the risk of cardiovascular disease and diabetes. Vascular dysfunction contributes to atherogenesis and has been linked to insulin resistance. METHODS AND RESULTS: We measured insulin sensitivity by glucose tolerance test and vascular function by ultrasound and venous occlusion plethysmography in 20 healthy subjects (14 men, 6 women) at baseline and during 5 days of bed rest. Bed rest led to a 67% increase in the insulin response to glucose loading (P<0.001) suggesting increased insulin resistance and produced increases in total cholesterol and triglycerides. Bed rest led to decreased reactive hyperemia in the forearm (1317+/-404 to 1112+/-260 mL/min, P=0.01) and the calf (28.5+/-7.0 to 22.2+/-8.7 mL/min/dL, P=0.003) indicating impaired microvascular function. Bed rest decreased brachial artery diameter and increased systolic blood pressure suggesting increased basal arterial tone. There were no changes in circulating inflammatory markers arguing against systemic inflammation as a mechanism for vascular dysfunction in this setting. CONCLUSIONS: Physical inactivity was associated with the development of insulin resistance, dyslipidemia, increased blood pressure, and impaired microvascular function in healthy volunteers. Our findings may provide insight into the pathogenesis of vascular disease in sedentary individuals and emphasize that even short-term physical inactivity may have adverse metabolic and vascular consequences.

Predictive value of reactive hyperemia for cardiovascular events in patients with peripheral arterial disease undergoing vascular surgery.

OBJECTIVE: Reactive hyperemia is the compensatory increase in blood flow that occurs after a period of tissue ischemia, and this response is blunted in patients with cardiovascular risk factors. The predictive value of reactive hyperemia for cardiovascular events in patients with atherosclerosis and the relative importance of reactive hyperemia compared with other measures of vascular function have not been previously studied. METHODS AND RESULTS: We prospectively measured reactive hyperemia and brachial artery flow-mediated dilation by ultrasound in 267 patients with peripheral arterial disease referred for vascular surgery (age 66+/-11 years, 26% female). Median follow-up was 309 days (range 1 to 730 days). Fifty patients (19%) had an event, including cardiac death (15), myocardial infarction (18), unstable angina (8), congestive heart failure (6), and nonhemorrhagic stroke (3). Patients with an event were older and had lower hyperemic flow velocity (75+/-39 versus 95+/-50 cm/s, P=0.009). Patients with an event also had lower flow-mediated dilation (4.5+/-3.0 versus 6.9+/-4.6%, P<0.001), and when these 2 measures of vascular function were included in the same Cox proportional hazards model, lower hyperemic flow (OR 2.7, 95% CI 1.2 to 5.9, P=0.018) and lower flow-mediated dilation (OR 4.2, 95% CI: 1.8 to 9.8, P=0.001) both predicted cardiovascular events while adjusting for other risk factors. CONCLUSIONS: Thus, lower reactive hyperemia is associated with increased cardiovascular risk in patients with peripheral arterial disease. Furthermore, flow-mediated dilation and reactive hyperemia incrementally relate to cardiovascular risk, although impaired flow-mediated dilation was the stronger predictor in this population. These findings further support the clinical relevance of vascular function measured in the microvasculature and conduit arteries in the upper extremity.

Effect of combined treatment with alpha-Lipoic acid and acetyl-L-carnitine on vascular function and blood pressure in patients with coronary artery disease.

Mitochondria produce reactive oxygen species that may contribute to vascular dysfunction. alpha-Lipoic acid and acetyl-L-carnitine reduce oxidative stress and improve mitochondrial function. In a double-blind crossover study, the authors examined the effects of combined alpha-lipoic acid/acetyl-L-carnitine treatment and placebo (8 weeks per treatment) on vasodilator function and blood pressure in 36 subjects with coronary artery disease. Active treatment increased brachial artery diameter by 2.3% (P=.008), consistent with reduced arterial tone. Active treatment tended to decrease systolic blood pressure for the whole group (P=.07) and had a significant effect in the subgroup with blood pressure above the median (151+/-20 to 142+/-18 mm Hg; P=.03) and in the subgroup with the metabolic syndrome (139+/-21 to 130+/-18 mm Hg; P=.03). Thus, mitochondrial dysfunction may contribute to the regulation of blood pressure and vascular tone. Further studies are needed to confirm these findings and determine the clinical utility of alpha-lipoic acid/acetyl-L-carnitine as antihypertensive therapy.

Effects of systemic inflammation on endothelium-dependent vasodilation.

The importance of inflammation in the pathogenesis of atherosclerosis is well established. The vascular endothelium contributes to and is affected by the inflammatory process. For example, a variety of cytokines have the ability to "activate" the endothelium and thereby promote expression of adhesion molecules and chemotactic factors that accelerate the inflammatory process and direct accumulation of leukocytes to specific sites in the arterial tree. In experimental systems, activation of endothelial cells is also associated with a loss of the biologic activity of endothelium-derived nitric oxide, an effect that accelerates the inflammatory process and also promotes local thrombosis and impairs local control of vasomotor tone. Consistent with these experimental studies, recent studies have provided evidence that inflammation is associated with an impairment of nitric oxide-dependent responses in human subjects. This article will review the experimental and clinical studies that support the relevance of inflammation to nitric oxide bioactivity in human atherosclerosis.

Near-infrared autofluorescence induced by intraplaque hemorrhage and heme degradation as marker for high-risk atherosclerotic plaques.

Atherosclerosis is a major cause of mortality and morbidity, which is mainly driven by complications such as myocardial infarction and stroke. These complications are caused by thrombotic arterial occlusion localized at the site of high-risk atherosclerotic plaques, of which early detection and therapeutic stabilization are urgently needed. Here we show that near-infrared autofluorescence is associated with the presence of intraplaque hemorrhage and heme degradation products, particularly bilirubin by using our recently created mouse model, which uniquely reflects plaque instability as seen in humans, and human carotid endarterectomy samples. Fluorescence emission computed tomography detecting near-infrared autofluorescence allows in vivo monitoring of intraplaque hemorrhage, establishing a preclinical technology to assess and monitor plaque instability and thereby test potential plaque-stabilizing drugs. We suggest that near-infrared autofluorescence imaging is a novel technology that allows identification of atherosclerotic plaques with intraplaque hemorrhage and ultimately holds promise for detection of high-risk plaques in patients.Atherosclerosis diagnosis relies primarily on imaging and early detection of high-risk atherosclerotic plaques is important for risk stratification of patients and stabilization therapies. Here Htun et al. demonstrate that vulnerable atherosclerotic plaques generate near-infrared autofluorescence that can be detected via emission computed tomography.