Clinical characteristics and management of coexistent cardiomyopathy in patients with bicuspid aortic valve.

BACKGROUND: Bicuspid aortic valve (BAV) is the most common congenital heart disease. However, the prevalence, clinical characteristics, and current management of BAV associated with inherited cardiomyopathy, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and left ventricular noncompaction (LVNC) have not been well described. METHODS: Consecutive patients diagnosed with BAV at a large tertiary cardiovascular referral center between 2009 and 2018 were retrospectively assessed for HCM, DCM, and LVNC based on clinical and echocardiographic criteria. Patients with coexistent conditions were investigated further. RESULTS: Of 3533 patients with BAV screened, 57 (1.6%) had concomitant cardiomyopathy. BAV was combined with HCM in 30 of these patients, with DCM in 19, and with LVNC in eight. Forty-six patients (80.7%) were male, and the mean age at first diagnosis was 47 years for BAV with HCM, 49 years for BAV with DCM, and 35 years for BAV with LVNC. Heart failure and aortic valve dysfunction were common in these patients, and the prevalence of coexisting aortopathy was 43.3%, 26.3% and 25.0%, respectively, for BAV with HCM, DCM and LVNC. During the index hospitalization, 24 of the 57 patients (42.1%) underwent surgery, 16 (28%) underwent aortic valve and/or aortic surgery, and 16 of the 30 patients with HCM had a Morrow procedure. There were no deaths or other major adverse cardiovascular events. CONCLUSIONS: The prevalence of inherited cardiomyopathy was higher in our patients with BAV than in the general population. Aortopathy and heart failure were common, with almost half of patients requiring surgery at diagnosis.

A novel missense mutation in obscurin gene in a Chinese consanguineous family with left ventricular noncompaction.

BACKGROUND: Left ventricular noncompaction (LVNC) is an increasingly recognised cardiomyopathy of which a significant percentage are genetic in origin. The purpose of the present study was to identify potential pathogenic mutation leading to disease in a Chinese LVNC family. METHODS: A 3-generation family affected by LVNC was recruited. Clinical assessments were performed on available family members, with clinical examination, ECG, echocardiography and cardiac MRI. The proband (I-2), the proband's daughter (II-1, affected) and mother (III-1, unaffected) were selected for WGS. Sanger sequencing were performed in all of the 4 surviving family members. RESULTS: Combined whole genome sequencing with linkage analysis identified a novel missense mutation in the giant protein obscurin (OBSCN NM_001098623, c.C19063T), as the only plausible disease-causing variant that segregates with disease among the four surviving individuals, with interrogation of the entire genome excluding other potential causes. This c.C19063T missense mutation resulted in p.R6355W in the encoded OBSCN protein. It affected a highly conserved residue in the C terminus of the obscurin-B-like isoform between the PH and STKc domains, which was predicted to affect the function of the protein by different bioinformatics tools. CONCLUSIONS: Here we present clinical and genetic evidence implicating the novel R6355W missense mutation in obscurin as the cause of familial LVNC. This expands the spectrum of obscurin's roles in cardiomyopathies. It furthermore highlights that rare obscurin missense variants, currently often ignored or left uninterpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here. This study also provided new insights into the molecular basis of OBSCN mutation positive LVNC.

Corrigendum: Pathogenicity and Long-Term Outcomes of Liddle Syndrome Caused by a Nonsense Mutation of SCNN1G in a Chinese Family.

[This corrects the article DOI: 10.3389/fped.2022.887214.].

Pathogenicity and Long-Term Outcomes of Liddle Syndrome Caused by a Nonsense Mutation of SCNN1G in a Chinese Family.

Objective: Liddle syndrome (LS) is a monogenic hypertension consistent with autosomal dominant inheritance, often with early onset high blood pressure in childhood or adolescence. This study aimed to identify the pathogenicity of a nonsense mutation in SCNN1G in a Chinese family with LS and the long-term outcomes of tailored treatment with amiloride. Methods: To explore the pathogenicity of candidate variant reported in 2015 by our team, we constructed mutant and wild-type models in vitro and measured amiloride-sensitive current in Chinese Hamster Ovary (CHO) cells using patch clamp technique. Participants were followed up for 7 years after tailored treatment with amiloride. Results: A nonsense variant was detected in six members, two of whom were pediatric patients. This mutation resulted in a termination codon at codon 572, truncating the Pro-Pro-Pro-X-Tyr motif. The mutant epithelial sodium channels displayed higher amiloride-sensitive currents than the wild-type channels (P < 0.05). Tailored treatment with amiloride achieved ideal blood pressure control in all patients with normal cardiorenal function, and no adverse events occurred during follow-up. Conclusion: We found the pathogenicity of a nonsense SCNN1G mutation (p.Glu571*) with enhanced amiloride-sensitive currents in a LS family with young patients. Tailored treatment with amiloride may be an effective strategy for the long-term control of blood pressure and protection from target organ damage or cardiovascular events, including children and youth patients with LS.

Implication of a novel truncating mutation in titin as a cause of autosomal dominant left ventricular noncompaction.

BACKGROUND: Mutation in the titin gene (TTN) in left ventricular noncompaction (LVNC) has been reported with a highly heterogeneous prevalence, and the molecular mechanisms underlying the pathogenesis of TTN gene mutation are uncharacterized. In the present study, we identified a novel TTN mutation in a pedigree with LVNC and investigated the potential pathogenic mechanism by functional studies. METHODS: The whole-genome sequencing with linkage analysis was performed in a 3-generation family affected by autosomal dominant LVNC cardiomyopathy. The clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR/Cas9) technology was used to establish novel truncating mutation in TTN in a rat cardiomyoblast H9C2 cell line in vitro, in which functional studies were carried out and characterized in comparison to its wild-type counterpart. RESULTS: A novel truncating mutation TTN p. R2021X was identified as the only plausible disease-causing variant that segregated with disease among the five surviving affected individuals, with an interrogation of the entire genome excluding other potential causes. Quantitative reverse transcription-polymerase chain reaction and cellular immunofluorescence supported a haploinsufficient disease mechanism in titin truncation mutation cardiomyocytes. Further functional studies suggested mitochondrial abnormities in the presence of mutation, including decreased oxygen consumption rate, reduced adenosine triphosphate production, impaired activity of electron translation chain, and abnormal mitochondrial structure on electron microscopy. Impaired autophagy under electron microscopy accompanied with activation of the Akt-mTORC1 signaling pathway was observed in TTN p. R2021X truncation mutation cardiomyocytes. CONCLUSIONS: The TTN p. R2021X mutation has a function in the cause of a highly penetrant familial LVNC. These findings expand the spectrum of titin's roles in cardiomyopathies and provide novel insight into the molecular basis of titin-truncating variants-associated LVNC.

Pulmonary enhancement imaging with dual energy CT for the detection of pulmonary embolism in a rabbit model: comparison to perfusion planar scintigraphy, SPECT and SPECT-CT modalities.

RATIONALE AND OBJECTIVES: Pulmonary enhancement imaging (PEI) derived from dual-energy computed tomographic (CT) imaging has been used to detect perfusion defects from pulmonary embolism (PE). The purpose of this study was to compare the ability of PEI, planar, single photon-emission CT (SPECT) perfusion scintigraphy, and SPECT-CT fusion images to detect perfusion defect in a PE rabbit model. MATERIALS AND METHODS: A PE model was made by injecting Gelfoam into the femoral veins of rabbits (n = 16). After 2 hours, 16 experimental rabbits and three control rabbits underwent contrast-enhanced dual-energy CT scans, from which PEI and CT pulmonary angiography were created, and planar, SPECT, and SPECT-CT fusion images were then obtained and evaluated. Pathologic determination of locations and numbers of lung lobes with PE were recorded. The sensitivity and specificity of the above-mentioned modalities were calculated using the histopathologic results as reference standards. RESULTS: Emboli were present in 31 pulmonary lobes and absent in 64 lung lobes in histopathologic analysis. With the histopathologic findings as the gold standard, sensitivities and specificities of PEI, planar, SPECT, and SPECT-CT fusion images to detect PE were 100% and 96.9%, 71.0% and 84.4%, 77.4% and 90.6%, and 74.2% and 93.8%, respectively. McNemar's tests showed that PEI had higher diagnostic accuracy for the detection of PE than three scintigraphic images (all P values < .05), while three scintigraphic images had similar diagnostic accuracy (all P values = NS). CONCLUSIONS: This study demonstrates that PEI from dual-energy CT imaging can provide higher diagnostic accuracy for detecting PE than planar, SPECT, and SPECT-CT fusion images in a rabbit model.

Detection of pulmonary embolism by dual energy CT: correlation with perfusion scintigraphy and histopathological findings in rabbits.

The purpose of the study was to compare the ability of dual energy CT (DECT) and perfusion scintigraphy (PS) to detect pulmonary embolism (PE) in a rabbit model. Gelfoam (n = 20) or saline (n = 4) was injected into the femoral vein of rabbits. After 2 h, DECT pulmonary angiography (CTPA) was used to create blood flow imaging (BFI) and fusion images. The rabbits then underwent PS. Pathological determination of locations and numbers of lung lobes with PE was recorded. The sensitivity and specificity for BFI, CTPA, fused images and PS were calculated using the pathological results as reference standards. Compared with pathological evaluation, CTPA correctly identified PE in 40 lobes and absence of emboli in 80 lobes, corresponding to a sensitivity and specificity of 100%. BFI and fused images correctly identified PE in 40 lobes and the absence of emboli in 78 lobes, corresponding to a sensitivity and specificity of 100% and 98%, respectively. PS correctly detected 27 lobes with PE and 65 lobes without PE, corresponding to a sensitivity and specificity of 68% and 81%, respectively. BFI, CTPA and fused images derived from a single contrast-enhanced DECT provide a higher diagnostic accuracy of detecting PE than PS in a rabbit model.