A Dual-Adjuvanted Parenteral-Intranasal Subunit Nanovaccine generates Robust Systemic and Mucosal Immunity Against SARS-CoV-2 in Mice.

Existing parenteral SARS-CoV-2 vaccines produce only limited mucosal responses, essential for reducing transmission and achieving sterilizing immunity. Appropriately designed mucosal boosters can overcome the shortcomings of parenteral vaccines and enhance pre-existing systemic immunity. Here, a new protein subunit nanovaccine is developed by utilizing dual-adjuvanted (RIG-I: PUUC RNA and TLR-9: CpG DNA) polysaccharide-amino acid-lipid nanoparticles (PAL-NPs) along with SARS-CoV-2 S1 trimer protein, that can be delivered both intramuscularly (IM) and intranasally (IN) to generate balanced mucosal-systemic SARS-CoV-2 immunity. Mice receiving IM-Prime PUUC+CpG PAL subunit nanovaccine, followed by an IN-Boost, developed high levels of IgA, IgG, and cellular immunity in the lungs and showed robust systemic humoral immunity. Interestingly, as a purely intranasal subunit vaccine (IN-Prime/IN-Boost), PUUC+CpG PAL-NPs induced stronger lung-specific T cell immunity than IM-Prime/IN-Boost, and a comparable IgA and neutralizing antibodies, although with a lower systemic antibody response, indicating that a fully mucosal delivery route for SARS-CoV-2 vaccination may also be feasible. The data suggest that PUUC+CpG PAL subunit nanovaccine is a promising candidate for generating SARS-CoV-2 specific mucosal immunity.

High- versus low-gradient aortic stenosis: Is our evaluation limited by aorto-mitral angle on cardiovascular CT?

BACKGROUND: Accurate assessment of aortic valve (AV) stenosis (AS) on transthoracic echocardiogram is crucial for appropriate clinical management. However, discordance between aortic valve area (AVA) and Doppler can complicate the diagnosis of severe AS in low-gradient (LG) AS phenotypes. METHODS: We reviewed 220 consecutive patients with suspected severe AS and AVA ≤1.0 cm2 on transthoracic echocardiogram who were evaluated for transcatheter AV replacement (TAVR) within a large health system from 2015 to 2019. We compared AV calcium score and aorto-mitral angle (AMA) on 3-chamber views from ECG-gated cardiovascular CT among patients with high-gradient (HG) AS (N = 19), paradoxical low-flow low-gradient (PLFLG) AS (N = 24) and normal-flow low-gradient (NFLG) AS (N = 14). RESULTS: All groups had comparable age, comorbidities, and AV calcium scores. Compared to patients with HG AS (mean AMA 120 ± 10°), those with PLFLG AS (104 ± 12°; p < 0.001) and NFLG AS (106 ± 13°; p = 0.008) had narrower mean AMA values on cardiovascular CT. CONCLUSION: LG AS patients have significantly narrower AMA than HG AS patients on cardiovascular CT. Due to difficulty obtaining parallel Doppler alignment, narrower AMA may contribute to AVA-Doppler discordance on echocardiogram. These findings emphasize the need for additional information in the setting of LG AS.

Intimomedial tears of the aorta heal by smooth muscle cell-mediated fibrosis without atherosclerosis.

BACKGROUNDDisease of the aorta varies from atherosclerosis to aneurysms, with complications including rupture, dissection, and poorly characterized limited tears. We studied limited tears without any mural hematoma, termed intimomedial tears, to gain insight into aortic vulnerability to excessive wall stresses. Our premise is that minimal injuries in aortas with sufficient medial resilience to prevent tear progression correspond to initial mechanisms leading to complete structural failure in aortas with significantly compromised medial resilience.METHODSIntimomedial tears were macroscopically identified in 9 of 108 ascending aortas after surgery and analyzed by histology and immunofluorescence confocal microscopy.RESULTSNonhemorrhagic, nonatheromatous tears correlated with advanced aneurysmal disease and most lacked distinctive symptoms or radiological signs. Tears traversed the intima and part of the subjacent media, while the resultant defects were partially or completely filled with neointima characterized by differentiated smooth muscle cells, scattered leukocytes, dense fibrosis, and absent elastic laminae despite tropoelastin synthesis. Healed lesions contained organized fibrin at tear edges without evidence of plasma and erythrocyte extravasation or lipid accumulation.CONCLUSIONThese findings suggest a multiphasic model of aortic wall failure in which primary lesions of intimomedial tears either heal if the media is sufficiently resilient or progress as dissection or rupture by medial delamination and tear completion, respectively. Moreover, mural incorporation of thrombus and cellular responses to injury, two historically important concepts in atheroma pathogenesis, contribute to vessel wall repair with adequate conduit function, but even together are not sufficient to induce atherosclerosis.FUNDINGNIH (R01-HL146723, R01-HL168473) and Yale Department of Surgery.

Factors associated with reporting left ventricular ejection fraction with 3D echocardiography in real-world practice.

BACKGROUND: Guidelines recommend 3D echocardiography (3DE) to assess left ventricular ejection fraction (LVEF) on transthoracic echocardiogram (TTE) when possible, but it is unclear which factors are most strongly associated with reporting 3DE LVEF in real-world practice. METHODS: We evaluated 3DE LVEF reporting by age, sex, BMI, TTE location and variation in reporting by sonographer and reader. All TTEs were performed without contrast enhancement agent at a large medical center from 9/2015 to 12/2020 using ultrasound machines capable of 3DE. We used multivariable logistic regression to assess which factors were most associated with reporting 3DE LVEF. RESULTS: Among 35 641 TTEs included in this study, 57.4% were performed on women. 3DE LVEF was reported on 18 391 TTEs (51.6% of cohort; 50.5% for women and 52.4% for men). Portable inpatient TTEs (n = 5569) had the lowest rates of 3DE LVEF reporting (30.9%), while general outpatient TTEs (n = 15 933) had greater reporting (56.9%). Outpatient TTEs with an indication for chemotherapy (n = 3244) had the highest rates of 3DE LVEF (87.2%). The median (IQR) percentage of TTEs reporting 3D LVEF was 52.7% (43.1%-68.1%) among sonographers and 51.6% (46.5%-59.6%) among readers. Among 20082 (56.3%) TTEs with 3DE LVEF measured by sonographers, 91.6% were included by readers in the final report. After adjustment, performing sonographer in the highest reporting quartile was most strongly associated with reporting 3DE LVEF (OR 7.04, 95% CI 6.55-7.56), while an inpatient portable study had the strongest negative association for reporting (OR .38, 95% CI .35-.40). CONCLUSIONS: Use of 3DE LVEF in real-world practice varies substantially based on performing sonographer and is low for hospitalized patients, but can be frequently used for chemotherapy. Initiatives are needed to increase sonographer 3DE acquisition in most clinical settings.

A multiadjuvant polysaccharide-amino acid-lipid (PAL) subunit nanovaccine generates robust systemic and lung-specific mucosal immune responses against SARS-CoV-2 in mice.

Existing parenteral SARS-CoV-2 vaccines produce only limited mucosal responses, which are essential for reducing transmission and achieving sterilizing immunity. Appropriately designed mucosal boosters could overcome the shortcomings of parenteral vaccines and enhance pre- existing systemic immunity. Here we present a new protein subunit nanovaccine using multiadjuvanted (e.g. RIG-I: PUUC, TLR9: CpG) polysaccharide-amino acid-lipid nanoparticles (PAL-NPs) that can be delivered both intramuscularly (IM) and intranasally (IN) to generate balanced mucosal-systemic SARS-CoV-2 immunity. Mice receiving IM-Prime PUUC+CpG PAL- NPs, followed by an IN-Boost, developed high levels of IgA, IgG, and cellular immunity in the lung, and showed robust systemic humoral immunity. Interestingly, as a purely intranasal vaccine (IN-Prime/IN-Boost), PUUC+CpG PAL-NPs induced stronger lung-specific T cell immunity than IM-Prime/IN-Boost, and a comparable IgA and neutralizing antibodies, although with a lower systemic antibody response, indicating that a fully mucosal delivery route for SARS-CoV-2 vaccination may also be feasible. Our data suggest that PUUC+CpG PAL-NP subunit vaccine is a promising candidate for generating SARS-CoV-2 specific mucosal immunity.

Contemporary cardiovascular computed tomography (CCT) training: Serial surveys of the international CCT community by the Fellow and Resident Leaders of the Society of Cardiovascular Computed Tomography (SCCT) Committee (FiRST) and SCCT Future Leaders Program (FLP).

BACKGROUND: As cardiovascular computed tomography (CCT) practice evolves, the demand for specialists continues to increase. However, CCT training remains variable globally with limited contemporaneous data to understand this heterogeneity. We sought to understand the role of CCT globally and the training available to underpin its use. METHODS: We performed two consecutive surveys of cardiology and radiology physicians, two years apart, utilizing the Society of Cardiovascular Computed Tomography (SCCT) website, weblinks, social media platforms, and meeting handouts to maximize our response rate. We compared United States (US)-based vs. international responses to understand global similarities and differences in practice and training in the surveys. RESULTS: 235 respondents (37% trainees and 63% educators/non-trainees) initiated the first survey with 174 (74%) completing the core survey, with 205 providing their work location (114 US and 91 international). Eighty-four percent (92/110) of educator respondents stated a need for increased training opportunities to meet growing demand. Dedicated training fellowships are heterogenous, with limited access to structural heart imaging training, despite structural scanning being performed within institutions. The lack of a standardized curriculum was identified as the main obstacle to effective CCT learning, particularly in the US, with web-based learning platforms being the most popular option for improving access to CCT training. 148 trainees initiated the second survey with 107 (72%) completing the core components (51% North America, 49% international). Only 68% said they would be able to meet their required CCT education needs via their training program. Obstacles in obtaining CCT training again included a lack of a developed curriculum (51%), a lack of dedicated training time (35%), and a lack of local faculty expertise (31%). There was regional variability in access to CCT training, and, in contrast to the first survey, most (89%) felt 1:1 live review of cases with trained/expert reader was most useful for improving CCT training alongside formal curriculum/live lectures (72%). CONCLUSIONS: There is a need to expand dedicated CCT training globally to meet the demand for complex CCT practice. Access to CCT education (didactic and 1:1 case-based teaching from expert faculty), implementation of recently published global training curricula, and increased teaching resources (web-based) as an adjunct to existing experiential learning opportunities, are all deemed necessary to address current educational shortfalls.

Tricuspid and mitral remodelling in atrial fibrillation: a three-dimensional echocardiographic study.

AIMS: Atrial fibrillation (AF) is associated with atrial enlargement, mitral annulus (MA) and tricuspid annulus (TA) dilation, and atrial functional regurgitation (AFR). However, less is known about the impact of AF on both atrioventricular valves in those with normal and abnormal ventricular function. We aimed to compare the remodelling of the TA and MA in patients with non-valvular AF without significant AFR. METHODS AND RESULTS: Ninety-two patients referred for transoesophageal echocardiography were included and categorized into three groups: (i) AF with normal left ventricular (LV) function (Normal LV-AF), n = 36; (ii) AF with LV systolic dysfunction (LVSD-AF), n = 29; and (iii) Controls in sinus rhythm, n = 27. Three-dimensional MA and TA geometry were analysed using automated software. In patients with AF regardless of LV function, the MA and TA areas were larger compared with controls (LVSD-AF vs. Normal LV-AF vs. Controls, end-systolic MA: 5.2 ± 1.1 vs. 4.5 ± 0.7 vs. 3.9 ± 0.7 cm2/m2; end-systolic TA: 5.6 ± 1.3 vs. 5.3 ± 1.3 vs. 4.1 ± 0.7 cm2/m2; P < 0.05 for each comparison with Controls). TA and MA areas were not statistically different between the two AF groups. The TA increase over controls was greater than that of the MA in the Normal LV-AF group (27.7% vs. 15.6%, P = 0.041). Conversely, in the LVSD-AF group, MA and TA increased similarly (35.9% vs. 32.4%, P = 0.660). CONCLUSION: Patients with AF showed dilation of both TA and MA compared with patients in sinus rhythm. In patients with normal LV function, AF was associated with greater TA dilation than MA dilation whereas in patients with LVSD the TA and MA were equally dilated.

Growth rate of ascending thoracic aortic aneurysms in a non-referral-based population.

BACKGROUND: Prior studies on ascending thoracic aortic aneurysm (ATAA) growth rates have reported approximately 1 mm of growth per year but these studies are based on referral-based study populations which are biased towards the highest risk patients who may not represent the true natural history of aortic aneurysm disease. We aimed to characterize the growth rate of ATAAs in a non-referral-based population, using a large institutional database of computed tomography (CT) scans. METHODS: We queried the 21,325 CT scans performed at our institution between 2013 and 2016 on patients ages 50-85 years old for radiologic diagnosis of aortic aneurysm or dilatation. 560 patients were identified to have aortic dilatation > 4 cm, of which 207 had follow-up scan intervals > 6 months. This comprised our non-referral-based study population. Linearized annual aneurysm growth rates were calculated by dividing the change in aortic size by the time interval between CT scans. RESULTS: The median time interval between scans was 2.7 years (interquartile range [IQR] 1.5-4.2) for the 207 patients included in the study. The median initial aneurysm size was 4.3 cm (IQR 4.1-4.5). 38.2% (n = 79) of patients did not experience aortic dilatation. The median growth rate was 0.13 mm/year (IQR - 0.24 to 0.49). Of patients in the top quartile of growth rates, 26.9% of patients were female whereas 12.9% of patients were female in the bottom three quartiles of growth rates. CONCLUSION: While some patients' ATAAs may grow at previously published rates of around 1 mm/year, this is not the predominant pattern in a non-referral-based population and may over-estimate the overall growth rate of ATAAs.

The utility of radiographic assessment of the internal mammary arteries in chest wall irradiated patients.

PURPOSE: The internal mammary arteries (IMA's) are historically recognized to be protected against atherosclerosis. Whether chest wall-irradiation for breast cancer leads to significant IMA damage remains unclear. The utility of computed tomography (CT) and mammography to detect radiation-induced damage to the IMA's and its branches is not known. The objective of this study is to assess the susceptibility of IMA's to radiation-induced atherosclerosis, and the utility of CT scan and mammography in the assessment of IMA and its branches. METHODS: A retrospective analysis of breast cancer patients who received chest wall-radiotherapy was performed. Patients with CT scans and/or mammograms ≥5 years post-radiotherapy were included. Baseline characteristics, coronary artery calcification (CAC), the presence of IMA damage assessed by CT scan, and IMA branch calcifications by mammography were recorded. RESULTS: None of the 66 patients with CT scans post-radiotherapy revealed IMA atherosclerosis. There were 28 (42.4%) patients with CAC, of which four (14.3% of CAC subgroup or 6.1% of the total cohort) had calcifications on either side on mammogram (Chi-square test, p = 0.74). Out of the 222 patients with mammograms, 36 (16.2%) had IMA branch calcifications. Two hundred and ten patients received unilateral radiotherapy, and 27 (12.9%) of these patients had calcifications on the irradiated side, and 26 patients (12.4%) had calcifications on the contralateral side (OR = 1.0). CONCLUSION: IMA's do not exhibit signs of radiation-induced atherosclerosis when evaluated by CT scan. In addition, there is no association between radiotherapy for breast cancer and the presence of IMA branch calcification on mammograms.

Integration of three-dimensional echocardiography into the modern-day echo laboratory.

Three-dimensional echocardiography (3DE) has emerged in recent decades from a conceptual, research tool to an important, useful imaging technique that can informatively impact daily clinical practice. However, its adoption into the modern-day echo laboratory requires the acknowledgment of its value, coupled with proper leadership, education, and resources to implement and integrate its use with conventional echo techniques. 3DE integration involves important updates regarding equipment and patient selection, assimilation of 3D protocols into current clinical routine, laboratory workflow adaptation, storage, and reporting. This review will provide a practical blueprint and key points of how to integrate 3DE into today's echo laboratory, necessary resources to implement 3D workflow, logistical challenges that remain, and future directions to further improve assimilation of this relevant echo technique into the laboratory.

Myopericarditis with Significant Left Ventricular Dysfunction Following COVID-19 Vaccination: A Case Report.

BACKGROUND Since Emergency Use Authorization of COVID-19 vaccines in December 2020, more is becoming known about their adverse effects. Growing numbers of myopericarditis cases after COVID-19 vaccination are being reported, mostly in younger adults. While most of these patients have recovered rapidly and without complications, it is still unclear whether patients who are older and have greater cardiac dysfunction secondary to myopericarditis will also experience the same recovery. CASE REPORT We report the case of a middle-aged man with myopericarditis and significant left ventricular dysfunction after the second dose of the Pfizer/BioNTech BNT162b2 COVID-19 vaccine. He presented several days after vaccination, and with non-steroidal anti-inflammatory treatment, he quickly recovered ventricular function, and symptoms resolved within 1 week after vaccination. CONCLUSIONS Vaccines are a key tool in combating the COVID-19 pandemic, yet many people are hesitant to seek vaccination, perhaps for fear of adverse events. Our report of a middle-aged patient with significant left ventricular dysfunction, who still experienced rapid recovery, should reassure the public about the safety of vaccines. Such rare adverse effects should not deter people from receiving COVID-19 vaccination.

Understanding the role of left and right ventricular strain assessment in patients hospitalized with COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) can cause cardiac injury resulting in abnormal right or left ventricular function (RV/LV) with worse outcomes. We hypothesized that two-dimensional (2D) speckle-tracking assessment of LV global longitudinal strain (GLS) and RV free wall strain (FWS) by transthoracic echocardiography can assist as markers for subclinical cardiac injury predicting increased mortality. METHODS: We performed 2D strain analysis via proprietary software in 48 patients hospitalized with COVID-19. Clinical information, demographics, comorbidities, and lab values were collected via retrospective chart review. The primary outcome was in-hospital mortality based on an optimized abnormal LV GLS value via ROC analysis and RV FWS. RESULTS: The optimal LV GLS cutoff to predict death was -13.8%, with a sensitivity of 85% (95% CI 55-98%) and specificity of 54% (95% CI 36-71%). Abnormal LV GLS >-13.8% was associated with a higher risk of death [unadjusted hazard ratio 5.15 (95% CI 1.13-23.45), p = 0.034], which persisted after adjustment for clinical variables. Among patients with LV ejection fraction (LVEF) >50%, those with LV GLS > -13.8% had higher mortality compared to those with LV GLS <-13.8% (41% vs. 10%, p = 0.030). RV FWS value was higher in patients with LV GLS >-13.8% (-13.7 ±â€¯5.9 vs. -19.6 ±â€¯6.7, p = 0.003), but not associated with decreased survival. CONCLUSION: Abnormal LV strain with a cutoff of >-13.8% in patients with COVID-19 is associated with significantly higher risk of death. Despite normal LVEF, abnormal LV GLS predicted worse outcomes in patients hospitalized with COVID-19. There was no mortality difference based on RV strain.

Multimodality Imaging in the Diagnosis of Prosthetic Valve Endocarditis: A Brief Review.

Infective endocarditis is a common and treatable condition that carries a high mortality rate. Currently the workup of infective endocarditis relies on the integration of clinical, microbiological and echocardiographic data through the use of the modified Duke criteria (MDC). However, in cases of prosthetic valve endocarditis (PVE) echocardiography can be normal or non-diagnostic in a high proportion of cases leading to decreased sensitivity for the MDC. Evolving multimodality imaging techniques including leukocyte scintigraphy (white blood cell imaging), 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), multidetector computed tomographic angiography (MDCTA), and cardiac magnetic resonance imaging (CMRI) may each augment the standard workup of PVE and increase diagnostic accuracy. While further studies are necessary to clarify the ideal role for each of these imaging techniques, nevertheless, these modalities hold promise in determining the diagnosis, prognosis, and care of PVE. We start by presenting a clinical vignette, then evidence supporting various modality strategies, balanced by limitations, and review of formal guidelines, when available. The article ends with the authors' summary of future directions and case conclusion.