Advances in Clinical Imaging of Vascular Inflammation: A State-of-the-Art Review.

Vascular inflammation is a major contributor to cardiovascular disease, particularly atherosclerotic disease, and early detection of vascular inflammation may be key to the ultimate reduction of residual cardiovascular morbidity and mortality. This review paper discusses the progress toward the clinical utility of noninvasive imaging techniques for assessing vascular inflammation, with a focus on coronary atherosclerosis. A discussion of multiple modalities is included: computed tomography (CT) imaging (the major focus of the review), cardiac magnetic resonance, ultrasound, and positron emission tomography imaging. The review covers recent progress in new technologies such as the novel CT biomarkers of coronary inflammation (eg, the perivascular fat attenuation index), new inflammation-specific tracers for positron emission tomography-CT imaging, and others. The strengths and limitations of each modality are explored, highlighting the potential for multi-modality imaging and the use of artificial intelligence image interpretation to improve both diagnostic and prognostic potential for common conditions such as coronary artery disease.

The evolving role of cholesteryl ester transfer protein inhibition beyond cardiovascular disease.

The main role of cholesteryl ester transfer protein (CETP) is the transfer of cholesteryl esters and triglycerides between high-density lipoprotein (HDL) particles and triglyceride-rich lipoprotein and low-density lipoprotein (LDL) particles. There is a long history of investigations regarding the inhibition of CETP as a target for reducing major adverse cardiovascular events. Initially, the potential effect on cardiovascular events of CETP inhibitors was hypothesized to be mediated by their ability to increase HDL cholesterol, but, based on evidence from anacetrapib and the newest CETP inhibitor, obicetrapib, it is now understood to be primarily due to reducing LDL cholesterol and apolipoprotein B. Nevertheless, evidence is also mounting that other roles of HDL, including its promotion of cholesterol efflux, as well as its apolipoprotein composition and anti-inflammatory, anti-oxidative, and anti-diabetic properties, may play important roles in several diseases beyond cardiovascular disease, including, but not limited to, Alzheimer's disease, diabetes, and sepsis. Furthermore, although Mendelian randomization analyses suggested that higher HDL cholesterol is associated with increased risk of age-related macular degeneration (AMD), excess risk of AMD was absent in all CETP inhibitor randomized controlled trial data comprising over 70,000 patients. In fact, certain HDL subclasses may, in contrast, be beneficial for treating the retinal cholesterol accumulation that occurs with AMD. This review describes the latest biological evidence regarding the relationship between HDL and CETP inhibition for Alzheimer's disease, type 2 diabetes mellitus, sepsis, and AMD.

Deep-Learning for Epicardial Adipose Tissue Assessment With Computed Tomography: Implications for Cardiovascular Risk Prediction.

BACKGROUND: Epicardial adipose tissue (EAT) volume is a marker of visceral obesity that can be measured in coronary computed tomography angiograms (CCTA). The clinical value of integrating this measurement in routine CCTA interpretation has not been documented. OBJECTIVES: This study sought to develop a deep-learning network for automated quantification of EAT volume from CCTA, test it in patients who are technically challenging, and validate its prognostic value in routine clinical care. METHODS: The deep-learning network was trained and validated to autosegment EAT volume in 3,720 CCTA scans from the ORFAN (Oxford Risk Factors and Noninvasive Imaging Study) cohort. The model was tested in patients with challenging anatomy and scan artifacts and applied to a longitudinal cohort of 253 patients post-cardiac surgery and 1,558 patients from the SCOT-HEART (Scottish Computed Tomography of the Heart) Trial, to investigate its prognostic value. RESULTS: External validation of the deep-learning network yielded a concordance correlation coefficient of 0.970 for machine vs human. EAT volume was associated with coronary artery disease (odds ratio [OR] per SD increase in EAT volume: 1.13 [95% CI: 1.04-1.30]; P = 0.01), and atrial fibrillation (OR: 1.25 [95% CI: 1.08-1.40]; P = 0.03), after correction for risk factors (including body mass index). EAT volume predicted all-cause mortality (HR per SD: 1.28 [95% CI: 1.10-1.37]; P = 0.02), myocardial infarction (HR: 1.26 [95% CI:1.09-1.38]; P = 0.001), and stroke (HR: 1.20 [95% CI: 1.09-1.38]; P = 0.02) independently of risk factors in SCOT-HEART (5-year follow-up). It also predicted in-hospital (HR: 2.67 [95% CI: 1.26-3.73]; P ≤ 0.01) and long-term post-cardiac surgery atrial fibrillation (7-year follow-up; HR: 2.14 [95% CI: 1.19-2.97]; P ≤ 0.01). CONCLUSIONS: Automated assessment of EAT volume is possible in CCTA, including in patients who are technically challenging; it forms a powerful marker of metabolically unhealthy visceral obesity, which could be used for cardiovascular risk stratification.

The effect of CETP inhibitors on new-onset diabetes: a systematic review and meta-analysis.

BACKGROUND: Despite the increasing prevalence of type 2 diabetes mellitus (T2DM), limited pharmacologic options are available for prevention. Cholesteryl ester transfer protein inhibitors (CETPis) have been studied primarily as a therapy to reduce cardiovascular disease, but have also been shown to reduce new-onset diabetes. As new trial data have become available, this meta-analysis examines the effect of CETP inhibitors on new-onset diabetes and related glycaemic measures. METHODS AND RESULTS: We searched MEDLINE, EMBASE, and Cochrane databases (all articles until 4 March, 2021) for randomised controlled trials (RCT) ≥1-year duration, with at least 500 participants, comparing CETPi to placebo, and that reported data on new-onset diabetes or related glycaemic measures [haemoglobin A1C (HbA1C), fasting plasma glucose, insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)]. A fixed effects meta-analysis model was applied to all eligible studies to quantify the effect of CETPi therapy on new-onset diabetes. Four RCTs (n = 75 102) were eligible for quantitative analysis of the effect of CETPi on new-onset diabetes. CETPis were found to significantly decrease the risk of new-onset diabetes by 16% (RR: 0.84; 95% CI: 0.78, 0.91; P < 0.001), with low between-trial heterogeneity (I2 = 4.1%). Glycaemic measures were also significantly improved or trended towards improvement in those with and without diabetes across most trials. CONCLUSION: Although RCTs have shown mixed results regarding the impact of CETPi on cardiovascular disease, they have shown a consistent reduction in the risk of new-onset diabetes with CETPi therapy. Future trials of CETPis and potentially other HDL-raising agents should therefore specify new-onset diabetes and reversal of existing T2DM as secondary endpoints.

Do the newly proposed realignment targets for C2 and T1 slope bridge the gap between radiographic and clinical success in corrective surgery for adult cervical deformity?

OBJECTIVE: Surgical correction of cervical deformity (CD) has been associated with superior alignment and functional outcomes. It has not yet been determined whether baseline or postoperative T1 slope (T1S) and C2 slope (C2S) correlate with health-related quality-of-life (HRQoL) metrics and radiographic complications, such as distal junctional kyphosis (DJK) and distal junctional failure (DJF). The objective of this study was to determine the impact of T1S and C2S deformity severity on HRQoL metrics and DJF development in patients with CD who underwent a cervical fusion procedure. METHODS: All operative CD patients with upper instrumented vertebra above C7 and preoperative (baseline) and up to 2-year postoperative radiographic and HRQoL data were included. CD was defined as meeting at least one of the following radiographic parameters: C2-7 lordosis < -15°, TS1-cervical lordosis mismatch > 35°, segmental cervical kyphosis > 15° across any 3 vertebrae between C2 and T1, C2-7 sagittal vertical axis > 4 cm, McGregor's slope > 20°, or chin-brow vertical angle > 25°. Spearman's rank-order correlation and linear regression analysis assessed the impact of T1S and C2S on HRQoL metrics (Neck Disability Index [NDI], modified Japanese Orthopaedic Association [mJOA] scale, EuroQOL 5-Dimension Questionnaire [EQ-5D] visual analog scale [VAS] score, and numeric rating scale [NRS]-neck) and complications (DJK, DJF, reoperation). Logistic regression and a conditional inference tree (CIT) were used to determine radiographic thresholds for achieving optimal clinical outcome, defined as meeting good clinical outcome criteria (≥ 2 of the following: NDI < 20 or meeting minimal clinically important difference, mild myelopathy [mJOA score ≥ 14], and NRS-neck ≤ 5 or improved by ≥ 2 points), not undergoing reoperation, or developing DJF or mechanical complication by 2 years. RESULTS: One hundred five patients with CD met inclusion criteria. By surgical approach, 14.7% underwent an anterior-only approach, 46.1% a posterior-only approach, and 39.2% combined anterior and posterior approaches. The mean baseline radiographic parameters were T1S 28.3° ± 14.5° and C2S 25.9° ± 17.5°. Significant associations were found between 3-month C2S and mJOA score (r = -0.248, p = 0.034), NDI (r = 0.399, p = 0.001), EQ-5D VAS (r = -0.532, p < 0.001), NRS-neck (r = 0.239, p = 0.040), and NRS-back (r = 0.264, p = 0.021), while significant correlation was also found between 3-month T1S and mJOA score (r = -0.314, p = 0.026), NDI (r = 0.445, p = 0.001), EQ-5D VAS (r = -0.347, p = 0.018), and NRS-neck (r = 0.269, p = 0.049). A significant correlation was also found between development of DJF and 3-month C2S (odds ratio [OR] 1.1, 95% confidence interval [CI] 1.01-1.1, p = 0.015) as well as for T1S (OR 1.1, 95% CI 1.01-1.1, p = 0.023). Logistic regression with CIT identified thresholds for optimal outcome by 2 years: optimal 3-month T1S < 26° (OR 5.6) and C2S < 10° (OR 10.4), severe 3-month T1S < 45.5° (OR 0.2) and C2S < 38.0° (no patient above this threshold achieved optimal outcome; all p < 0.05). Patients below both optimal thresholds achieved rates of 0% for DJK and DJF, and 100% met optimal outcome. CONCLUSIONS: The severity of CD, defined by T1S and C2S at baseline and especially at 3 months, can be predictive of postoperative functional improvement and occurrence of worrisome complications in patients with CD, necessitating the use of thresholds in surgical planning to achieve optimal outcomes.

Post-void bladder ultrasound in suspected cauda equina syndrome-data from medicolegal cases and relevance to magnetic resonance imaging scanning.

OBJECTIVE: Post-void residual (PVR) scans of less than 200 ml are increasingly being used to rule out the likelihood of cauda equina syndrome (CES) and to delay emergency MRI scanning in suspected cases. This study was done to review a series of 50 MRI confirmed cases of CES and to test the hypothesis that a PVR of less than 200 ml was unlikely to be present. METHODS: Fifty consecutive medicolegal cases involving CES were audited. Records were reviewed to see if PVR scans were done. MRI scans were reviewed, clinical and radiological diagnosis reviewed, and treatment recorded. RESULTS: Out of 50 CES cases, 26 had had PVR scans. In 14/26 (54%) the PVR scan was ≤ 200 ml. In one case, the CES diagnosis was in question leaving 13/26 (50%) cases where there was a clear clinical and MRI diagnosis of CES despite the PVR being ≤ 200 ml. All 13 were classified as incomplete cauda equina syndrome (CESI) and all proceeded to emergency decompression. CONCLUSIONS: This study is the first in the literature to demonstrate that there is a significant group of CES patients who require emergency decompression but have PVRs ≤ 200 ml. The results demonstrate the existence of a significant group of CESI patients whose bladder function may be deteriorating, but they have not yet reached the point where the PVR is over 200 ml. Given the accepted understanding that CESI is best treated with emergency decompression, such patients are likely to have worse outcomes if MRI scanning and therefore surgery is delayed. We recommend the following: PVR is recommended as an assessment tool in suspected CES. A PVR of ≤ 200 reduces the likelihood of having CES but does not exclude it; clinical suspicion of CES should always lead to an MRI scan. Further investigation of PVR as a prognostic tool is recommended.

Cauda equina syndrome-a practical guide to definition and classification.

PURPOSE: International uniformity of definition and classification are crucial for diagnosis and management of cauda equina syndrome (CES). They are also useful for clinicians when discussing CES with patients and relatives, and for medicolegal purposes. METHODS: We reviewed published literature using PubMed on definition and classification of cauda equina syndrome since 2000 (21 years). Using the search terms 'cauda equina' and 'definition' or 'classification', we found and reviewed 212 papers. RESULTS: There were 17 different definitions of CES used in the literature. There were three well-defined methods of classification of CES. The two-stage system of incomplete CES (CESI) versus CES with retention (CESR) is the most commonly used classification, and has prognostic value although the details of this continue to be debated. CONCLUSION: We used the existing literature to propose a clear definition of CES. We also drew on peer-reviewed published literature that has helped to amplify and expand the CESI/CESR dichotomy, adding categories that are both less severe than CESI, and more severe than CESR, and we propose clear definitions in a table form to assist current and future discussion and management of CES.

Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics.

Increased cardiac contractility during the fight-or-flight response is caused by ß-adrenergic augmentation of CaV1.2 voltage-gated calcium channels1-4. However, this augmentation persists in transgenic murine hearts expressing mutant CaV1.2 α1C and ß subunits that can no longer be phosphorylated by protein kinase A-an essential downstream mediator of ß-adrenergic signalling-suggesting that non-channel factors are also required. Here we identify the mechanism by which ß-adrenergic agonists stimulate voltage-gated calcium channels. We express α1C or ß2B subunits conjugated to ascorbate peroxidase5 in mouse hearts, and use multiplexed quantitative proteomics6,7 to track hundreds of proteins in the proximity of CaV1.2. We observe that the calcium-channel inhibitor Rad8,9, a monomeric G protein, is enriched in the CaV1.2 microenvironment but is depleted during ß-adrenergic stimulation. Phosphorylation by protein kinase A of specific serine residues on Rad decreases its affinity for ß subunits and relieves constitutive inhibition of CaV1.2, observed as an increase in channel open probability. Expression of Rad or its homologue Rem in HEK293T cells also imparts stimulation of CaV1.3 and CaV2.2 by protein kinase A, revealing an evolutionarily conserved mechanism that confers adrenergic modulation upon voltage-gated calcium channels.