Left atrial volume: comparison of 2D and 3D transthoracic echocardiography with ECG-gated CT angiography.

RATIONALE AND OBJECTIVES: Left atrial volume (LAV) measurement by conventional two-dimensional (2D) transthoracic echocardiography (TTE) may be limited by the geometric model, by suboptimal definition of left atrial endocardium, or by chamber foreshortening. Three-dimensional (3D) TTE is posited to eliminate chamber foreshortening, and LAV measurement by 3D TTE should be more reflective of true LAV. The aim of this study was to compare conventional 2D TTE and newer 3D TTE for measurements of LAV to multidetector computed tomographic (MDCT) measurements using automated chamber reconstruction (ACR). MATERIALS AND METHODS: Twenty-two subjects consented to undergo 2D TTE and 3D TTE immediately prior to or following coronary computed tomographic angiography. LAV was calculated from 2D TTE using the area-length method (ALM) and from 3D TTE with the ALM as well as with a 3D model. Electrocardiographically gated coronary computed tomographic angiography was performed in helical mode. LAV was measured using the ALM as well as ACR. RESULTS: LAV was significantly smaller by 2D TTE (80 ± 21 mL) and 3D-TTE (90 ± 24 mL with the ALM, 61 ± 16 mL with the 3D model) compared to MDCT ACR (120 ± 30 mL) (P \u3c .01). Correlation between MDCT ALM and MDCT ACR was excellent (mean Δ = -1.4 ± 14 mL, r = 0.91). Correlation with MDCT ACR was no better for 3D TTE (r = 0.80) than for 2D TTE (r = 0.80). CONCLUSIONS: LAV is underestimated by both 2D TTE and 3D TTE relative to coronary computed tomographic angiography. Excellent agreement between the ALM and ACR with MDCT imaging suggests that the geometric model plays a negligible role in the underestimation of LAV. Underestimation of LAV by echocardiography is likely related to suboptimal definition of left atrial contour

Characterization and Normal Measurements of the Left Ventricular Outflow Tract by ECG-gated Cardiac CT: Implications for Disorders of the Outflow Tract and Aortic Valve.

RATIONALE AND OBJECTIVES: Studies suggest that electrocardiographically gated coronary computed tomographic angiography provides a clear definition of the left ventricular outflow tract (LVOT), and normal LVOT morphology may not be round, as assumed when the continuity equation is applied during echocardiography. The aims of this study were to demonstrate the morphology of the LVOT on coronary computed tomographic angiography and to establish normal values for LVOT measurements. MATERIALS AND METHODS: Two independent readers retrospectively measured anterior-posterior (AP) and transverse diameters of the LVOT and performed LVOT planimetry on coronary computed tomographic angiographic studies of 106 consecutive patients with normal aortic valves. RESULTS: Excellent interobserver agreement was observed for all measurements (r = 0.78-0.94). The LVOT was ovoid, with a larger transverse diameter than AP diameter during diastole and systole (P \u3c .001). However, the ratio of AP diameter to transverse diameter was closer to 1.0 during systole (P \u3c .001). Mean indexed LVOT area was minimally larger in systole than in diastole (P = .01-.04) and was larger in men than in women during diastole (P ≤ .001) and systole (P ≤ .01). Mean LVOT area indexed to body surface area was 2.3 ± 0.5 cm(2)/m(2) in women and 2.6 ± 0.7 cm(2)/m(2) in men. LVOT area demonstrated significant correlation with aortic root diameter. CONCLUSIONS: The normal LVOT is ovoid in shape. LVOT is more circular during systole, but the AP diameter remains smaller than the transverse diameter throughout the cardiac cycle. The oval shape of the LVOT has important implications when LVOT area is calculated from LVOT diameters. Normal LVOT area values established in this study should facilitate diagnosis of the fixed component of LVOT obstruction

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Rapid Development of a Papillary Fibroelastoma with Associated Thrombus: The Role of Transthoracic and Transesophageal Echocardiography.

Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) are frequently utilized in patient\u27s with suspected cerebral vascular ischemia. We describe a patient with suspected cerebral vascular ischemic event whom was found to have a mobile valvular mass by TTE and TEE. The lesion was unusual due to its rapid development over a period 6 months, which was documented on serial echocardiography. The mass was excised surgically and pathology showed a papillary fibroelastoma with extensive thrombus. The differential diagnosis of a cardiac valvular mass and the treatment of cardiac fibroelastomas are reviewed. In this case, both TTE and TEE were valuable in diagnosis and facilitating surgical management of a cardiac fibroelastoma

<em>De novo</em> mutations in SON disrupt RNA splicing of genes essential for brain development and metabolism, causing an intellectual-disability syndrome.

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and&nbsp;HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development