Stephanie L. Sellers

CD4+ T cells support cytotoxic T lymphocyte priming by controlling lymph node input.

Rapid induction of CD8+ cytotoxic T lymphocyte (CTL) responses is critical to combat acute infection with intracellular pathogens. CD4+ T cells help prime antigen-specific CTLs in secondary lymphoid organs after infection in the periphery. Although the frequency of naïve precursors is very low, the immune system is able to efficiently screen for cognate CTLs through mechanisms that are not well understood. Here we examine the role of CD4+ T cells in early phases of the immune response. We show that CD4+ T cells help optimal CTL expansion by facilitating entry of naïve polyclonal CD8+ T cells into the draining lymph node (dLN) early after infection or immunization. CD4+ T cells also facilitate input of naïve B cells into reactive LNs. Such “help” involves expansion of the arteriole feeding the dLN and enlargement of the dLN through activation of dendritic cells. In an antigen- and CD40-dependent manner, CD4+ T cells activate dendritic cells to support naïve lymphocyte recruitment to the dLN. Our results reveal a previously unappreciated mode of CD4+ T-cell help, whereby they increase the input of naïve lymphocytes to the relevant LN for efficient screening of cognate CD8+ T cells.

Caveolin as a potential drug target for cardiovascular protection

Caveolae and caveolin are key players in a number of disease processes. Current research indicates that caveolins play a significant role in cardiovascular disease and dysfunction. The far-reaching roles of caveolins in disease and dysfunction make them particularly notable therapeutic targets. In particular, caveolin-1 (Cav-1) and caveolin-3 (Cav-3) have been identified as potential regulators of vascular dysfunction and heart disease and might even confer cardiac protection in certain settings. Such a central role in vascular health therefore makes manipulation of Cav-1/3 function or expression levels clear therapeutic targets in a variety of cardiovascular related disease states. Here, we highlight the role of Cav-1 and Cav-3 in cardiovascular health and explore the potential of Cav-1 and Cav-3 derived experimental therapeutics.

Nitric oxide and TNFα are critical regulators of reversible lymph node vascular remodeling and adaptive immune response.

Lymph node (LN) vascular growth, at the level of the main arteriole, was recently characterized for the first time during infection. Arteriole diameter was shown to increase for at least seven days and to occur via a CD4+ T cell dependent mechanism, with vascular expansion playing a critical role in regulating induction of adaptive immune response. Here, using intravital microscopy of the inguinal LN during herpes simplex type II (HSV-2) infection, the data provides the first studies that demonstrate arteriole expansion during infection is a reversible vascular event that occurs via eutrophic outward remodeling. Furthermore, using genetic ablation models, and pharmacological blockade, we reveal arteriole remodeling and LN hypertrophy to be dependent upon both endothelial nitric oxide synthase (eNOS) and TNFα expression. Additionally, we reveal transient changes in nitric oxide (NO) levels to be a notable feature of response to viral infection and LN vascular remodeling and provide evidence that mast cells are the critical source of TNFα required to drive arteriole remodeling. Overall, this study is the first to fully characterize LN arteriole vascular changes throughout the course of infection. It effectively reveals a novel role for NO and TNFα in LN cellularity and changes in LN vascularity, which represent key advances in understanding LN vascular physiology and adaptive immune response.

Recombinant Decorin Fusion Protein Attenuates Murine Abdominal Aortic Aneurysm Formation and Rupture

Decorin (DCN) is a small-leucine rich proteoglycan that mediates collagen fibrillogenesis, organization, and tensile strength. Adventitial DCN is reduced in abdominal aortic aneurysm (AAA) resulting in vessel wall instability thereby predisposing the vessel to rupture. Recombinant DCN fusion protein CAR-DCN was engineered with an extended C-terminus comprised of CAR homing peptide that recognizes inflamed blood vessels and penetrates deep into the vessel wall. In the present study, the role of systemically-administered CAR-DCN in AAA progression and rupture was assessed in a murine model. Apolipoprotein E knockout (ApoE-KO) mice were infused with angiotensin II (AngII) for 28 days to induce AAA formation. CAR-DCN or vehicle was administrated systemically until day 15. Mortality due to AAA rupture was significantly reduced in CAR-DCN-treated mice compared to controls. Although the prevalence of AAA was similar between vehicle and CAR-DCN groups, the severity of AAA in the CAR-DCN group was significantly reduced. Histological analysis revealed that CAR-DCN treatment significantly increased DCN and collagen levels within the aortic wall as compared to vehicle controls. Taken together, these results suggest that CAR-DCN treatment attenuates the formation and rupture of Ang II-induced AAA in mice by reinforcing the aortic wall.

Imaging for structural heart procedures: focus on computed tomography

The success and continued rapid clinical integration of transcatheter valve technologies relies on imaging modalities to guide safe and effective device deployment. In particular, cardiac imaging, using both echocardiography and CT, is an integral resource for the multidisciplinary team. These modalities can provide valuable insight for the proceduralist at each stage of transcatheter-based valve insertion, as they can be used reliably to define the anatomy of interest and its relationship to surrounding structures, determine accurate device sizing, assess patients for valve-in-valve procedures, and screen for adverse features or procedural contraindications. We provide an overview of some of the key aspects of the use of CT and echocardiography in the context of transcatheter aortic valve replacement (TAVR), as well as transcatheter mitral valve replacement (TMVR).

Computed Tomography Imaging for Mitral Valve Regurgitation

The clinical utility of coronary computed tomography angiography for the evaluation of coronary artery disease is well established in routine cardiology practice. Advances in multidetector computed tomography (MDCT) technology over the past decade have seen dramatic improvements in both spatial and temporal resolution, which has permitted acquisition of high-quality images despite the challenges presented by cardiac motion. Above and beyond allowing for the comprehensive assessment of the epicardial coronary vessels, cardiac chamber contrast opacification with new-generation MDCT scanners also enables accurate and detailed segmentation of the left-sided cardiac valves. Traditional two-dimensional (2D) echocardiography has long been the reference standard for the diagnosis and evaluation of valvular pathology; however, transthoracic echocardiography (TTE) is operator dependent and can be limited in patients with poor acoustic windows, and transesophageal echocardiography (TEE) is invasive. Both approaches limit acquisition to a restricted number of planes/projections, which cannot be subsequently manipulated. In contrast, three-dimensional (3D) imaging techniques such as MDCT permit rapid acquisition of volumetric datasets with unlimited 2D planar reconstruction post-processing capability. This recent development in MDCT technology has fortunately paralleled the rapid expansion of percutaneous valvular repair strategies for patients with symptomatic severe valvular heart disease who are deemed inoperable.

Hypertrophic Cardiomyopathy (HCM): New insights into Coronary artery remodelling and ischemia from FFRCT

INTRODUCTION Angina, myocardial ischemia, and coronary artery physiology in hypertrophic cardiomyopathy (HCM) are poorly understood. However, coronary computed tomography angiography (CCTA) with fractional flow reserve from CT (FFRCT) analysis offers a non-invasive method for evaluation of coronary artery volume to myocardial mass ratio (V/M) that may provide insight into such mechanisms. Thus, we sought to investigate changes in V/M in HCM. METHODS A retrospective analysis was performed on 37 HCM patients and 37 controls matched for age, sex, and cardiovascular risk factors; CCTA-derived coronary artery lumen volume (V) and myocardial mass (M) were used to determine V/M. FFRCT values were calculated for the left anterior descending (LAD), left circumflex (LCx) and right coronary (RCA) arteries as well as the 3-vessel cumulative FFRCT values. RESULTS HCM patients had significantly increased myocardial mass (176 ± 84 vs. 119 ± 27 g, p < 0.0001) and total coronary artery luminal volume (4112 ± 1139 vs. 3290 ± 924 mm3, p < 0.0001) that resulted from increases in segmented luminal volumes of both the left and right coronary artery systems. However, HCM patients had significantly decreased V/M (23.8 ± 5.9 vs. 26.5 ± 5.3 mm3/g; p = 0.026) which was further decreased when restricting V/M analysis to those HCM patients with septal hypertrophy (22.4 mm3/g, p = 0.01) that was mild-moderately predictive of HCM (AUC = 0.68). HCM patients also showed significantly lower nadir FFRCT values in the LCx (0.87 ± 0.06 vs. 0.91 ± 0.06, p = 0.02), and cumulative 3-vessel FFRCT values (2.58 ± 0.18 vs. 2.63 ± 0.14, p = 0.006). CONCLUSIONS HCM patients demonstrate significantly greater coronary volume. Despite this, HCM patients suffer from decreased V/M. Further prospective studies evaluating the relationship between V/M, angina, and heart failure in HCM are needed.

Impact of Non-obstructive left main disease on the progression of coronary artery disease: A PARADIGM substudy

BACKGROUND The aim of the study is examine the impact of non-obstructive (<50%stenosis) left main (LM) disease on the natural history of coronary artery disease using serial coronary computed tomography angiography (CTA). METHODS CTAs from the PARADIGM (Progression of atherosclerotic plaque determined by computed tomographic angiography imaging) study, a prospective multinational registry of patients who underwent serial CTA at a ≥2 year interval were analyzed. Those without evidence of CAD on their baseline scan were excluded, as were those with obstructive left main disease. Coronary artery vessels and their branches underwent quantification of: plaque volume and composition; diameter stenosis; presence of high-risk plaque. RESULTS Of 944 (62 ± 9 years, 60% male) who had evidence of CAD at baseline, 444 (47%) had LM disease. Those with LM disease had a higher baseline plaque volume (194.8 ± 221mm3 versus 72.9 ± 84.3mm3, p < 0.001) and a higher prevalence of high-risk plaque (17.5% versus 13%, p < 0.001) than those without LM disease. On multivariable general linear model, patients with LM disease had greater annual rates of progression of total (26.5 ± 31.4mm3/yr versus 14.9 ± 20.1mm3/yr, p < 0.001) and calcified plaque volume (17 ± 24mm3/yr versus 7 ± 11mm3/yr, p < 0.001), with no difference in fibrous, fibrofatty or necrotic core plaque components. CONCLUSION The presence of non-obstructive LM disease is associated with greater rates of plaque progression and a higher prevalence of high-risk plaque throughout the entire coronary artery tree compared to CAD without LM involvement. Our data suggests that non-obstructive LM disease may be a marker for an aggressive phenotype of CAD that may benefit from more intensive treatment strategies.

Prevalence and impact of scan-related anxiety during coronary CT angiography: A prospective cohort study of 366 patients

BACKGROUND Scanxiety, the anxiety/stress associated with an imaging test, has never been evaluated in relation to coronary CT angiography (Coronary CTA). As it could impact heart rate and thereby affect image quality of Coronary CTA, we aimed to evaluate the prevalence, severity, and impact of scanxiety on quality and interpretability of Coronary CTA. METHODS 366 consecutive patients were prospectively presented with a clinical questionnaire comprising two tests to evaluate their scan-related anxiety: the Impact of Event IES-6 (6 questions, final score 0-24) and a visual stress-scale (1 question, score 1-10). Patient demographics, heart rate and final image quality scored by two readers were recorded. Potential independent correlations were sought between IES-6 scanxiety level and image quality, heart rate variability and demographics, using an ordinal logistic regression model. RESULTS 344 patients (59.9% men, 57.6 ± 10.7yo) completed the questionnaire. 74.1% (255 patients) reported some scan-related distress, with a mean IES-6 score of 4.1 ± 4.3 (range 0-18). There was no significant difference in terms of age, sex or indications for Coronary CTA between the non-anxious (IES-6 = 0) and the anxious (IES-6>0) patients. There was no significant independent correlation between image quality and IES-6 score (OR = 0.98, p = 0.62), nor between IES-6 score and heart rate variability (effect = -0.005, p = 0.97). CONCLUSION The prevalence of scan-related anxiety - aka scanxiety - in Coronary CTA patients is high (74.1%) but does not appear to impact image quality and interpretability.

Role of MDCT Imaging in Planning Mitral Valve Intervention

Purpose of ReviewRecent advancements in transcatheter valvular interventions have resulted in a growing demand for advanced cardiac imaging to help guide these procedures.Recent FindingsBoth echocardiography and multi-detector computed tomography have played essential roles in the maturation of transcatheter aortic valve replacement and are now building on these experiences and helping inform the nascent field of transcatheter mitral interventions.SummaryAdvanced imaging is essential to aid in the diagnosis and determination of the mechanism of mitral regurgitation. In addition, they are integral to annular sizing, determination of the suitability of patient anatomy for specific devices and increasingly important in the determination of the risk of left ventricular outflow tract obstruction and providing appropriate patient-specific fluoroscopic angulation in advance of the procedure.