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At the molecular level, AS also shares common features with atherosclerosis including lipid infiltration, inflammation, fibrosis and calcification in the subendothelial space and lamina fibrosa. Since lipoproteins are involved in several putative pathways in the development of AS, lipid-lowering agents such as statins would be expected to have a beneficial impact on AS progression due to their effect on inflammation and atherosclerosis, and yet randomised trials have shown no benefit of statin on AS progression despite a marked reduction in cholesterol levels in individuals with mild to moderate AS.3 High levels of lipoprotein(a) (Lp(a)), a lipoprotein structurally similar to low-density lipoprotein, have been associated with an increased risk of atherosclerosis and more recently AS. Recent enthusiasm in hybrid imaging particularly with 18F-sodium fluoride (18F-NaF) positron emission tomography (PET)/CT is based on the notion that it can provide both anatomic and molecular data. 18F-NaF uptake in calcified aortic valves has been shown to extend beyond areas of macrocalcification and to predict new area of calcium deposition and subsequent increase in AVC. [...]18F-NaF uptake not only correlates with AS severity, but it appears to be a measure of the pathological process of ongoing calcifying activity. Zheng et al showed that in patients with AS, elevated Lp(a) levels (>35 mg/dL) were associated with increased AVC activity measured by 18F-NaF uptake on PET/CT, increased progression of AVC, more rapid AS progression and increased risks of aortic valve replacement and death. 5 These findings suggest that Lp(a) lowering may be a good approach and 18F-NaF uptake a surrogate marker of progression in trials on prevention of AS progression.

ObjectiveThis study assessed whether apolipoprotein CIII-lipoprotein(a) complexes (ApoCIII-Lp(a)) associate with progression of calcific aortic valve stenosis (AS).MethodsImmunostaining for ApoC-III was performed in explanted aortic valve leaflets in 68 patients with leaflet pathological grades of 1–4. Assays measuring circulating levels of ApoCIII-Lp(a) complexes were measured in 218 patients with mild–moderate AS from the AS Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial. The progression rate of AS, measured as annualised changes in peak aortic jet velocity (Vpeak), and combined rates of aortic valve replacement (AVR) and cardiac death were determined. For further confirmation of the assay data, a proteomic analysis of purified Lp(a) was performed to confirm the presence of apoC-III on Lp(a).ResultsImmunohistochemically detected ApoC-III was prominent in all grades of leaflet lesion severity. Significant interactions were present between ApoCIII-Lp(a) and Lp(a), oxidised phospholipids on apolipoprotein B-100 (OxPL-apoB) or on apolipoprotein (a) (OxPL-apo(a)) with annualised Vpeak (all p<0.05). After multivariable adjustment, patients in the top tertile of both apoCIII-Lp(a) and Lp(a) had significantly higher annualised Vpeak (p<0.001) and risk of AVR/cardiac death (p=0.03). Similar results were noted with OxPL-apoB and OxPL-apo(a). There was no association between autotaxin (ATX) on ApoB and ATX on Lp(a) with faster progression of AS. Proteomic analysis of purified Lp(a) showed that apoC-III was prominently present on Lp(a).ConclusionApoC-III is present on Lp(a) and in aortic valve leaflets. Elevated levels of ApoCIII-Lp(a) complexes in conjunction with Lp(a), OxPL-apoB or OxPL-apo(a) identify patients with pre-existing mild–moderate AS who display rapid progression of AS and higher rates of AVR/cardiac death.Trial registration NCT00800800.

We assessed the left atrial-left ventricular (LA-LV) long axis angulation value as a new measure of LA remodeling, and studied its predictors, its effect on two-dimensional LA volume (2D LAVol) estimation, and optimization techniques for 2D LAVol values. Retrospective electrocardiogram-gated coronary computed tomographic angiograms of 164 consecutive patients were reviewed. The LA–LV angle was measured in reconstructed 3-chamber views, and its predictors were determined. The LAVol measured by the area-length method after image optimization along the LV long axis (AL) and the LA long axis (AC–AL), was compared with that measured by the three-dimensional (3D)-volumetric method. LAVol calculation was modified to minimize differences from the 3D values. LA–LV angles ranged from 0° to 63°. In the univariate analysis, decreasing angulation was significantly associated with increasing LV end-diastolic volume (LVEDV), mitral regurgitation grade, LV and LA anteroposterior dimensions, and decreasing LV ejection fraction (LVEF). On multivariate analysis, increasing LVEDV, MR, and LA anteroposterior dimension inversely correlated with angulation; LVEF was positively correlated. The AL and 3D methods significantly differed only for patients with angles ≤ 29.9°. Conversely, LAVol was overestimated for all angules by AC–AL. Modification of AL LAVol using a regression equation, or by substituting the shortest with the longest and average LA lengths in patients with angles ≤ 29.9° and 30–39.9°, respectively neutralized the difference. The LA–LV angle is a new measure of LA and LV remodeling predicted by LV size and function, MR, and LA-anteroposterior dimension. AL formula modifications based on angulation in LV-optimized views better correlate with the 3D method than LA-view modification.

Background Most high-throughput screening (HTS) systems studying the cytotoxic effect of chimeric antigen receptor (CAR) T cells on tumor cells rely on two-dimensional cell culture that does not recapitulate the tumor microenvironment (TME). Tumor spheroids, however, can recapitulate the TME and have been used for cytotoxicity assays of CAR T cells. But a major obstacle to the use of tumor spheroids for cytotoxicity assays is the difficulty in separating unbound CAR T and dead tumor cells from spheroids. Here, we present a three-dimensional hanging spheroid plate (3DHSP), which facilitates the formation of spheroids and the separation of unbound and dead cells from spheroids during cytotoxicity assays. Results The 3DHSP is a 24-well plate, with each well composed of a hanging dripper, spheroid wells, and waste wells. In the dripper, a tumor spheroid was formed and mixed with CAR T cells. In the 3DHSP, droplets containing the spheroids were deposited into the spheroid separation well, where unbound and dead T and tumor cells were separated from the spheroid through a gap into the waste well by tilting the 3DHSP by more than 20°. Human epidermal growth factor receptor 2 (HER2)-positive tumor cells (BT474 and SKOV3) formed spheroids of approximately 300–350 μm in diameter after 2 days in the 3DHSP. The cytotoxic effects of T cells engineered to express CAR recognizing HER2 (HER2-CAR T cells) on these spheroids were directly measured by optical imaging, without the use of live/dead fluorescent staining of the cells. Our results suggest that the 3DHSP could be incorporated into a HTS system to screen for CARs that enable T cells to kill spheroids formed from a specific tumor type with high efficacy or for spheroids consisting of tumor types that can be killed efficiently by T cells bearing a specific CAR. Conclusions The results suggest that the 3DHSP could be incorporated into a HTS system for the cytotoxic effects of CAR T cells on tumor spheroids. Graphical Abstract

The “athletic heart” is characterized by hypertrophy and dilation of the heart, in addition to functional and electrical remodeling. The aim of this study was to provide reference 2-dimensional (2DE) and 3-dimensional (3DE) echocardiographic measurements in a large database on draft-eligible elite ice hockey players and to determine the frequency of occult cardiac anomalies in this cohort of athletes. In this prospective cohort study, we performed a comprehensive cardiac assessment of the 100 top draft picks selected by the National Hockey League. Complete 2DE and 3DE examinations were performed to obtain comprehensive measurements of cardiac structure and function at rest, which were compared with nonathlete controls. A total of 592 athletes were evaluated (mean age 18 ± 0.5 years) from 2009 to 2014 at the National Hockey League combine. 2DE and 3DE ventricular, atrial dimensions, and left ventricular mass were significantly greater in the athletes compared with controls. Abnormalities were identified in 15 hockey players (2.5%) consisting of a bicuspid aortic valve in 10 (1.7%), patent ductus arteriosus in 1 (0.2%), low normal left ventricular systolic function in 2 (0.3%), an idiopathic pericardial effusion in 1 (0.2%), and posterior mitral valve prolapse in 1 (0.2%). In conclusion, intense ice hockey training is associated with typical myocardial adaptations and the frequency of cardiac anomalies found in this cohort of young elite hockey players is low and does not differ significantly from the reported incidences in the general population.

Objective: To investigate the impact of blood pressure (BP) on the Doppler echocardiographic (Doppler-echo) evaluation of severity of aortic stenosis (AS). Methods: Handgrip exercise or phenylephrine infusion was used to increase BP in 22 patients with AS. Indices of AS severity (mean pressure gradient (ΔPmean), aortic valve area (AVA), valve resistance, percentage left ventricular stroke work loss (% LVSW loss) and the energy loss coefficient (ELCo)) were measured at baseline, peak BP intervention and recovery. Results: From baseline to peak intervention, mean (SD) BP increased (99 (8) vs 121 (10) mm Hg, p<0.001), systemic vascular resistance (SVR) increased (1294 (264) vs 1552 (372) dyne×s/cm5, p<0.001) and mean (SD) transvalvular flow rate (Qmean) decreased (323 (67) vs 306 (66) ml/s, p = 0.02). There was no change in ΔPmean (36 (13) vs 36 (14) mm Hg, p = NS). However, there was a decrease in AVA (1.15 (0.32) vs 1.09 (0.33) cm2, p = 0.02) and ELCo (1.32 (0.40) vs 1.24 (0.42) cm2, p = 0.04), and an increase in valve resistance (153 (63) vs 164 (74) dyne×s/cm5, p = 0.02), suggesting a more severe valve stenosis. In contrast, % LVSW loss decreased (19.8 (6) vs 16.5 (6)%, p<0.001), suggesting a less severe valve stenosis. There was an inverse relationship between the change in mean BP and AVA (r =  –0.34, p = 0.02); however, only the change in Qmean was an independent predictor of the change in AVA (r = 0.81, p<0.001). Conclusions: Acute BP elevation due to increased SVR can affect the Doppler-echo evaluation of AS severity. However, the impact of BP on the assessment of AS severity depends primarily on the associated change in Qmean, rather than on an independent effect of SVR or arterial compliance, and can result in a valve appearing either more or less stenotic depending on the direction and magnitude of the change in Qmean.

Purpose of Review In patients with systemic lupus erythematosus (SLE), cardiovascular involvement is common and a major cause of morbidity and mortality. There have been few recent updates regarding the cardiac involvement in this clinical entity. The purpose of the review is to provide an update on the role of echocardiography in the management of these patients. Recent Findings Echocardiography remains the imaging modality of choice and should be considered even in asymptomatic patients with SLE to detect cardiac abnormalities which are frequently not clinically apparent. Transesophageal echocardiography has higher sensitivity and specificity in identifying valvular lesions, and should be utilized in high risk patients when transthoracic echocardiography is negative. New advances such as speckle tracking echocardiography has shown promise in the detection of occult myocardial dysfunction, but more studies are needed to have a proper perspective of its role in SLE patients. Summary SLE has protean cardiac manifestations. The most common involvement is pericarditis. Complicated pericarditis such as tamponade and constriction are rare but should be considered if the symptoms do not subside with treatment. Valvular involvement can take several forms. Libman-Sacks endocarditis is the most common form and is more prevalent in patients with high disease activity and with the presence of antisphopholipid antibodies. Myocardial involvement portends poor prognosis and should be sought and treated promptly to prevent morbidity and mortality.

BackgroundThe gold-standard treatment of severe mitral regurgitation (MR) due to degenerative disease is valve repair, which is surgically performed with either a leaflet resection or leaflet preservation approach. Recent data suggest that functional mitral stenosis (MS) may occur following valve repair using a leaflet resection strategy, which adversely affects patient prognosis. A randomised comparison of these two approaches to mitral repair on functional MS has not been conducted.Methods and analysisThis is a prospective, multicentre randomised controlled trial designed to test the hypothesis that leaflet preservation leads to better preservation of mitral valve geometry, and therefore, will be superior to leaflet resection for the primary outcome of functional MS as assessed by 12-month mean mitral valve gradient at peak exercise. Eighty-eight patients with posterior leaflet prolapse will be randomised intraoperatively once deemed by the operating surgeon to feasibly undergo mitral repair using either a leaflet resection or leaflet preservation approach. Secondary end points include comparison of repair strategies with regard to mitral valve orifice area, leaflet coaptation height, 6 min walk test and a composite major adverse event end point consisting of recurrent MR ≥2+, death or hospital readmission for congestive heart failure within 12 months of surgery.Ethics and disseminationInstitutional ethics approval has been obtained from all enrolling sites. Overall, there remains clinical equipoise regarding the mitral valve repair strategy that is associated with the least likelihood of functional MS. This trial hopes to introduce high-quality evidence to help surgical decision making in this context.Trial registration numberNCT02552771.

Perivalvular abscess is an ominous development in patients with infective endocarditis. There is little information concerning the long-term outcome of these patients. Patients admitted to a tertiary care centre in Ottawa between November 1987 and December 1995 because of infective endocarditis complicated by perivalvular abscess were identified by chart audit and by review of the transesophageal echocardiography database. The patients were followed for at least 4 years to determine cardiac complications, late cardiac surgery, long-term outcome and functional status. Forty-three consecutive patients with infective endocarditis and perivalvular abscess (32 men and 11 women; mean age 56 [standard deviation 16] years) were identified; 17 had native valve endocarditis and 26 had prosthetic valve endocarditis. Of the 43 patients, 31 had cardiac surgery during the hospital stay; 6 died in hospital, and 10 died during follow-up. Twelve patients received medical treatment alone; none died in hospital, and 8 died during follow-up. The medically treated patients had less severe heart failure than the surgically treated patients (p = 0.12), but the 2 groups were similar in age and infective organisms. After a mean of 4.5 years of follow-up, the cumulative death rate was 57%; survival was similar among the medically and surgically treated patients. The survivors were younger than the nonsurvivors (p = 0.04). Complications of perivalvular abscess, including pseudoaneurysms and fistulae, were common, occurring in all medically treated patients and in 10 of the 24 surgically treated patients who had follow-up transesophageal echocardiography. Patients with infective endocarditis and perivalvular abscess had a high rate of death after hospital discharge and a high incidence of complications of perivalvular abscess, despite early surgical intervention in most patients. Lower age was the only predictor of long-term survival.

This new addition will provide an update on the current prophylaxis guidelines, the new diagnostic approach in the detection of the disease, the proposed schemas to predict prognosis, and the new treatment strategies to improve the outcome of patients afflicted with this serious condition. Endocarditis is a serious disease with ahigh rate of morbidity and mortality. The in-hospital mortality remains at 10-20%. The poor outcome ofpatients with this condition is due in large part to the delay in making thediagnosis which frequently can be elusive. As a result of its wide spectrum of manifestations, endocarditis canmimic many different conditions ranging from stroke to renal failure. In order to minimize the delay in diagnosis,clinicians need to always be mindful of the possibility that endocarditis maybe the cause of the symptoms. There have been ongoing efforts in thedevelopment of molecular probes and new imaging techniques to improve ourability to identify the disease early and reliably. New treatment strategies have been studiedwith the aim to prevent complications and to improve survival.Thestructure of the previous edition is preserved. The book is divided into three sections with the first section coveringthe historical perspective and basic principles, the second section dealingwith the diagnosis and management approaches and the last section on specificclinical situations that pose management dilemmas. All the chapters will be updated to include newinformation from the recent studies. Inparticular, the approach to the use of antibiotic prophylaxis will beextensively revised to present and discuss the implications of the currentguidelines from different national societies including the American HeartAssociation and the British Society for Antimicrobial Chemotherapy.This update is timely and should be ofinterest to all clinicians involved in the care of patients with this seriousdisease. This new edition will be a good resource forinternists, infectious disease specialists, cardiologists and cardiac surgeonsalike .