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BACKGROUND AND PURPOSE: The ATP-dependent biliary efflux transporter ABCC2, also known as multidrug resistance protein 2 (MRP2), is essential for the cellular disposition and detoxification of various xenobiotics including drugs as well as endogenous metabolites. Common functionally relevant ABCC2 genetic variants significantly alter drug responses and contribute to side effects. The aim of this study was to determine functional consequences of rare variants identified in subjects with European ancestry using in silico tools and in vitro analyses. EXPERIMENTAL APPROACH: Targeted next-generation sequencing of the ABCC2 gene was used to identify novel variants in European subjects (n = 143). Twenty-six in silico tools were used to predict functional consequences. For biological validation, transport assays were carried out with membrane vesicles prepared from cell lines overexpressing the newly identified ABCC2 variants and estradiol ß-glucuronide and carboxydichlorofluorescein as the substrates. KEY RESULTS: Three novel rare ABCC2 missense variants were identified (W227R, K402T, V489F). Twenty-five in silico tools predicted W227R as damaging and one as potentially damaging. Prediction of functional consequences was not possible for K402T and V489F and for the common linked variants V1188E/C1515Y. Characterisation in vitro showed increased function of W227R, V489F and V1188E/C1515Y for both substrates, whereas K402T function was only increased for carboxydichlorofluorescein. CONCLUSION AND IMPLICATIONS: In silico tools were unable to accurately predict the substrate-dependent increase in function of ABCC2 missense variants. In vitro biological studies are required to accurately determine functional activity to avoid misleading consequences for drug therapy.
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BACKGROUND: Detailed visualization and precise measurements of aortic valve dimensions are critical for the success of transcatheter aortic valve implantation and for the prevention of complications. Currently, multislice computed tomography is the gold standard for assessment of the aortic annulus and surrounding structures to determine the prosthesis size. New technologies such as virtual reality (VR) not only enable 3-dimensional (3D) visualization with the potential to improve understanding of anatomy and pathology but also allow measurements in 3D. This study aims to investigate the feasibility, accuracy, and reproducibility of VR for the visualization of the aortic valve, the surrounding structures, and its role in preprocedural sizing for transcatheter aortic valve implantation. METHODS AND RESULTS: Based on the preprocedural multislice computed tomography data, 3mensio measurements and 3D visualizations and measurements using VR software were performed retrospectively on 60 consecutive patients who underwent transcatheter aortic valve implantation at our heart center. There were no significant differences but strong correlations between the VR measurements compared with those performed with the 3mensio software. Furthermore, excellent or good intra- and interobserver reliability could be demonstrated for all values. In a structured questionnaire, users reported that VR simplified anatomical understanding, improved 3D comprehension of adjacent structures, and was associated with very good self-perceived depth perception. CONCLUSIONS: The use of VR for preprocedural transcatheter aortic valve implantation sizing is feasible and has precise and reproducible measurements. In addition, 3D visualization improves anatomical understanding and orientation. To evaluate the potential benefits of 3D visualization for planning further cardiovascular interventions, research in this field is needed.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Estudios de Factibilidad , Prótesis Valvulares Cardíacas , Imagenología Tridimensional , Tomografía Computarizada Multidetector , Reemplazo de la Válvula Aórtica Transcatéter , Realidad Virtual , Humanos , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Reproducibilidad de los Resultados , Masculino , Femenino , Reemplazo de la Válvula Aórtica Transcatéter/métodos , Reemplazo de la Válvula Aórtica Transcatéter/instrumentación , Anciano de 80 o más Años , Anciano , Estudios Retrospectivos , Estenosis de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Diseño de Prótesis , Variaciones Dependientes del Observador , Valor Predictivo de las Pruebas , Interpretación de Imagen Radiográfica Asistida por ComputadorRESUMEN
Background: Bifemoral arterial access is common in patients undergoing transcatheter aortic valve implantation (TAVI), with a primary treatment access (TAVI access) and a secondary non-TAVI access. Pseudoaneurysm (PSA) is an important complication of femoral arterial puncture. Major vascular complications after TAVI are well described, but little is known about PSA. Patients and methods: A total of 2063 patients underwent transfemoral TAVI between January 2014 and January 2020. Vascular ultrasound of the common femoral artery was assessed before and after TAVI. We compared patient characteristics, periprocedural risk scores, procedural characteristics, and access site bleeding events according to Valve Academic Research Consortium 3 (VARC-3) criteria, length of stay (LOS), and all-cause mortality at one year between patients with (46) and without (2017) PSA. Results: The incidence of PSA after TAVI was 2.2% (46/2063). All PSA were successfully treated with ultrasound-guided manual compression (UGMC) or thrombin injection (UGTI) without complications. Patients with PSA had lower platelet counts (210×1000/µl vs. 234×1000/µl; p<0.05), more heart failure symptoms on admission (91% vs. 25%; p<0.05), were more often treated with (N)OACs for atrial fibrillation (AF; 54% vs. 38%; p <0.05), and were less often treated with aspirin (35% vs. 51%; p<0.03). Multivariate analysis identified secondary access site (odds ratio [OR] 8.11; p<0.001) and (N)OAC therapy (OR 1.31; p = 0.037) as risk factors for PSA development. PSA is associated with VARC-3 type 1-3 access site bleeding and longer LOS (15.2 ± 11.3 d vs. 11.6 ± 8.9 d; p<0.01), but this did not affect one year mortality (17% vs. 14%; p = 0.53). Conclusions: Pseudoaneurysms are an important complication after TAVI and are associated with access site bleeding and prolonged hospital stay. (N)OAC therapy and secondary access are important risk factors. Pseudoaneurysms can be safely and effectively treated with thrombin injection and do not affect one-year mortality.
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Due to the complex and variable anatomy of the left atrial appendage, percutaneous left atrial appendage closure (LAAC) can be challenging. In this study, we investigated the impact of fusion imaging (FI) on the LAAC learning curve of two interventionalists. The first interventionalist (IC 1) was initially trained without FI and continued his training with FI. The second interventionalist (IC 2) performed all procedures with FI. We compared the first 36 procedures without FI of IC 1 (group 1) with his next 36 interventions with FI (group 2). Furthermore, group 1 was compared to 36 procedures of IC 2 who directly started his training with FI (group 3). Group 1 demonstrated that the learning curve without FI has a flat course with weak correlations for fluoroscopy time, contrast volume, and procedure time, but not for dose area product. Group 2 with FI showed improvement with a steep course and strong correlations for all four parameters. In group 3, we also saw a steep progression with strong correlations. Furthermore, the mean measurements of the parameters in the groups with FI decreased significantly as an indicator of procedural efficacy. We demonstrated that FI may improve the learning curve of experienced and non-experienced ICs.
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In a genome-wide association study of atorvastatin pharmacokinetics in 158 healthy volunteers, the SLCO1B1 c.521T>C (rs4149056) variant associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) of atorvastatin (P = 1.2 × 10-10), 2-hydroxy atorvastatin (P = 4.0 × 10-8), and 4-hydroxy atorvastatin (P = 2.9 × 10-8). An intronic LPP variant, rs1975991, associated with reduced atorvastatin lactone AUC0-∞ (P = 3.8 × 10-8). Three UGT1A variants linked with UGT1A3*2 associated with increased 2-hydroxy atorvastatin lactone AUC0-∞ (P = 3.9 × 10-8). Furthermore, a candidate gene analysis including 243 participants suggested that increased function SLCO1B1 variants and decreased activity CYP3A4 variants affect atorvastatin pharmacokinetics. Compared with individuals with normal function SLCO1B1 genotype, atorvastatin AUC0-∞ was 145% (90% confidence interval: 98-203%; P = 5.6 × 10-11) larger in individuals with poor function, 24% (9-41%; P = 0.0053) larger in those with decreased function, and 41% (16-59%; P = 0.016) smaller in those with highly increased function SLCO1B1 genotype. Individuals with intermediate metabolizer CYP3A4 genotype (CYP3A4*2 or CYP3A4*22 heterozygotes) had 33% (14-55%; P = 0.022) larger atorvastatin AUC0-∞ than those with normal metabolizer genotype. UGT1A3*2 heterozygotes had 16% (5-25%; P = 0.017) smaller and LPP rs1975991 homozygotes had 34% (22-44%; P = 4.8 × 10-5) smaller atorvastatin AUC0-∞ than noncarriers. These data demonstrate that genetic variation in SLCO1B1, UGT1A3, LPP, and CYP3A4 affects atorvastatin pharmacokinetics. This is the first study to suggest that LPP rs1975991 may reduce atorvastatin exposure. [Correction added on 6 April, after first online publication: An incomplete sentence ("= 0.017) smaller in heterozygotes for UGT1A3*2 and 34% (22%, 44%; P × 10-5) smaller in homozygotes for LPP noncarriers.") has been corrected in this version.].
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Área Bajo la Curva , Atorvastatina , Citocromo P-450 CYP3A , Estudio de Asociación del Genoma Completo , Glucuronosiltransferasa , Transportador 1 de Anión Orgánico Específico del Hígado , Polimorfismo de Nucleótido Simple , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Atorvastatina/farmacocinética , Atorvastatina/sangre , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Genotipo , Glucuronosiltransferasa/genética , Voluntarios Sanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/sangre , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Variantes Farmacogenómicas , Proteínas con Dominio LIM/genética , Proteínas del Citoesqueleto/genéticaRESUMEN
The hepatic content of amyloid beta (Aß) decreases drastically in human and rodent cirrhosis highlighting the importance of understanding the consequences of Aß deficiency in the liver. This is especially relevant in view of recent advances in anti-Aß therapies for Alzheimer's disease (AD). Here, it is shown that partial hepatic loss of Aß in transgenic AD mice immunized with Aß antibody 3D6 and its absence in amyloid precursor protein (APP) knockout mice (APP-KO), as well as in human liver spheroids with APP knockdown upregulates classical hallmarks of fibrosis, smooth muscle alpha-actin, and collagen type I. Aß absence in APP-KO and deficiency in immunized mice lead to strong activation of transforming growth factor-ß (TGFß), alpha secretases, NOTCH pathway, inflammation, decreased permeability of liver sinusoids, and epithelial-mesenchymal transition. Inversely, increased systemic and intrahepatic levels of Aß42 in transgenic AD mice and neprilysin inhibitor LBQ657-treated wild-type mice protect the liver against carbon tetrachloride (CCl4)-induced injury. Transcriptomic analysis of CCl4-treated transgenic AD mouse livers uncovers the regulatory effects of Aß42 on mitochondrial function, lipid metabolism, and its onco-suppressive effects accompanied by reduced synthesis of extracellular matrix proteins. Combined, these data reveal Aß as an indispensable regulator of cell-cell interactions in healthy liver and a powerful protector against liver fibrosis.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Hígado , Ratones Transgénicos , Animales , Humanos , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/genética , Modelos Animales de Enfermedad , Hígado/metabolismo , Hígado/patología , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Organotypic three-dimensional liver spheroid cultures in which hepatic cells retain their molecular phenotype and functionality have emerged as powerful tools for preclinical drug development. In recent years a multitude of culture systems have been developed; however, a thorough side-by-side benchmarking of the different methods is lacking. Here, we compared the performance of ten different 96- and 384-well microplate types to support spheroid formation and long-term culture. Specifically, we evaluated differences in spheroid formation kinetics, viability, functionality, expression patterns, and their utility for hepatotoxicity assessments using primary human hepatocytes (PHH) and primary canine hepatocytes (PCH). All 96-well plates enabled formation of PHH liver spheroids, albeit with differences between plates in spheroid size, geometry, and reproducibility. Performance of different 384-wells was less consistent. Only 6/10 microplates supported the formation of PCH aggregates. Interestingly, even if PCH aggregates in these six microplates were more loosely packed than PHH spheroids, they maintained their function and were compatible with long-term pharmacological and toxicological assays. Overall, Corning and Biofloat plates showed the best performance in the formation of both human and canine liver spheroids with highest viability, most physiologically relevant phenotypes, superior CYP activity and lowest coefficient of variation in toxicity assays. The presented data constitutes a valuable resource that demonstrates the impacts of current ultra-low attachment plates on liver spheroid metrics and can guide evidence-based plate selection. Combined, these results have important implications for the cross-comparison of different studies and can facilitate the standardization and reproducibility of three-dimensional liver culture experiments.
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Hepatocitos , Esferoides Celulares , Humanos , Animales , Perros , Reproducibilidad de los Resultados , Hepatocitos/metabolismo , Hígado , FenotipoRESUMEN
CYP3A4 activity shows considerable interindividual variability. Although studies indicate 60%-80% is heritable, common single nucleotide variants (SNVs) in CYP3A4 together only explain ~10%. Transcriptional factors, such as the testis-specific Y-encoded-like proteins (TSPYLs) family, have been reported to regulate the expression of CYP enzymes including CYP3A4 in vitro. Here, we investigated the effect of genetic variants in TSPYL on CYP3A4 activity using data from a clinical study and a human liver bank. Five SNVs (rs3828743, rs10223646, rs6909133, rs1204807, and rs1204811) in TSPYL were selected because of a reported effect on CYP3A4 expression in vitro or suggested clinical effect. For the clinical study, whole blood concentrations, clinical data, and DNA were available from 295 kidney transplant recipients participating in the prospective MECANO study. A multivariate pharmacokinetic model adjusted for body weight, steroid treatment, and CYP3A4 genotype was used to assess the effect of the genetic variants on cyclosporine clearance. In multivariate analysis, homozygous carriers of rs3828743 had a 18% lower cyclosporin clearance compared to the wild-type and heterozygous patients (28.72 vs. 35.03 L/h, p = 0.018) indicating a lower CYP3A4 activity and an opposite direction of effect compared to the previously reported increased CYP3A4 expression. To validate, we tested associations between rs3828743 and CYP3A4 mRNA and protein expression as well as enzyme activity with data from a liver bank (n = 150). No association with any of these end points was observed. In conclusion, the totality of evidence is not in support of a significant role for TSPYL SNV rs3828743 in explaining variability in CYP3A4 activity.
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Ciclosporina , Trasplante de Riñón , Masculino , Humanos , Ciclosporina/farmacocinética , Citocromo P-450 CYP3A/genética , Inmunosupresores/farmacocinética , Factores de Transcripción/genética , Trasplante de Riñón/efectos adversos , Estudios Prospectivos , Genotipo , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVES: Dynamic Coronary Roadmap (DCR) is a software tool that creates a real-time dynamic coronary artery overlay on fluoroscopic images. The efficacy of DCR in significantly reducing contrast medium use during percutaneous coronary interventions (PCI) has previously been shown. In this study, we aimed to determine if DCR is equally effective irrespective of the performing investigator's experience level. METHODS: In this sub-analysis of a monocentric, open-label, randomized trial, 130 patients with hemodynamic relevant coronary type A and B lesions were randomized and contrast medium use was conducted with (+) or without (-) DCR software. PCI was randomly allocated and performed by an investigator with high (A) or medium (B) experience level. RESULTS: Overall, contrast medium use was significantly reduced by both investigators in the +DCR group, and Investigator B used significantly less contrast medium with the software than Investigator A. The DCR software was not accompanied by increased radiation exposure for the patients or the teams. On the contrary, dose area product was reduced by both investigators, but was significantly reduced by the highly experienced investigator when using DCR. Fluoroscopy time was not different between investigators. Procedural success was 100%. Serious in-hospital adverse events were not observed. One of Investigator A's patients suffered from post-procedural acute kidney injury in the -DCR group. CONCLUSIONS: DCR significantly reduces contrast medium use during PCI irrespective of investigator's experience level.
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Lesión Renal Aguda , Intervención Coronaria Percutánea , Humanos , Intervención Coronaria Percutánea/efectos adversos , Diagnóstico por Imagen , Vasos Coronarios , Corazón , Medios de Contraste/efectos adversosRESUMEN
Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases, ranging from liver steatosis to metabolic dysfunction-associated steatohepatitis (MASH), increasing the risk of developing cirrhosis and hepatocellular carcinoma (HCC). Fibrosis within MASLD is critical for disease development; therefore, the identification of fibrosis-driving factors is indispensable. We analyzed the expression of interleukin 32 (IL-32) and chemokine CC ligand 20 (CCL20), which are known to be linked with inflammation and fibrosis, and for their expression in MASLD and hepatoma cells. RT-PCR, ELISA and Western blotting analyses were performed in both human liver samples and an in vitro steatosis model. IL-32 and CCL20 mRNA expression was increased in tissues of patients with NASH compared to normal liver tissue. Stratification for patatin-like phospholipase domain-containing protein 3 (PNPLA3) status revealed significance for IL-32 only in patients with I148M (rs738409, CG/GG) carrier status. Furthermore, a positive correlation was observed between IL-32 expression and steatosis grade, and between IL-32 as well as CCL20 expression and fibrosis grade. Treatment with the saturated fatty acid palmitic acid (PA) induced mRNA and protein expression of IL-32 and CCL20 in hepatoma cells. This induction was mitigated by the substitution of PA with monounsaturated oleic acid (OA), suggesting the involvement of oxidative stress. Consequently, analysis of stress-induced signaling pathways showed the activation of Erk1/2 and p38 MAPK, which led to an enhanced expression of IL-32 and CCL20. In conclusion, cellular stress in liver epithelial cells induced by PA enhances the expression of IL-32 and CCL20, both known to trigger inflammation and fibrosis.
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Hígado Graso , Hepatocitos , Enfermedades Metabólicas , Humanos , Carcinoma Hepatocelular/genética , Quimiocina CCL20/genética , Quimiocinas , Hepatocitos/metabolismo , Ligandos , Cirrosis Hepática/genética , Neoplasias Hepáticas/genética , Ácido Palmítico , Regulación hacia Arriba , Grasas Insaturadas/metabolismoRESUMEN
The therapeutic efficacy of tamoxifen is predominantly mediated by its active metabolites 4-hydroxy-tamoxifen and endoxifen, whose formation is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6). Yet, known CYP2D6 polymorphisms only partially determine metabolite concentrations in vivo. We performed the first cross-ancestry genome-wide association study with well-characterized patients of European, Middle-Eastern, and Asian descent (n = 497) to identify genetic factors impacting active and parent metabolite formation. Genome-wide significant variants were functionally evaluated in an independent liver cohort (n = 149) and in silico. Metabolite prediction models were validated in two independent European breast cancer cohorts (n = 287, n = 189). Within a single 1-megabase (Mb) region of chromosome 22q13 encompassing the CYP2D6 gene, 589 variants were significantly associated with tamoxifen metabolite concentrations, particularly endoxifen and metabolic ratio (MR) endoxifen/N-desmethyltamoxifen (minimal P = 5.4E-35 and 2.5E-65, respectively). Previously suggested other loci were not confirmed. Functional analyses revealed 66% of associated, mostly intergenic variants to be significantly correlated with hepatic CYP2D6 activity or expression (ρ = 0.35 to -0.52), and six hotspot regions in the extended 22q13 locus impacting gene regulatory function. Machine learning models based on hotspot variants (n = 12) plus CYP2D6 activity score (AS) increased the explained variability (~ 9%) compared with AS alone, explaining up to 49% (median R2 ) and 72% of the variability in endoxifen and MR endoxifen/N-desmethyltamoxifen, respectively. Our findings suggest that the extended CYP2D6 locus at 22q13 is the principal genetic determinant of endoxifen plasma concentration. Long-distance haplotypes connecting CYP2D6 with adjacent regulatory sites and nongenetic factors may account for the unexplained portion of variability.
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Neoplasias de la Mama , Citocromo P-450 CYP2D6 , Humanos , Femenino , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Estudio de Asociación del Genoma Completo , Antineoplásicos Hormonales/uso terapéutico , Tamoxifeno , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , GenotipoRESUMEN
BACKGROUND: Patient safety is one of the most important issues in healthcare. High-risk percutaneous coronary interventions (HR-PCIs) offer well-established treatment options for patients with complex coronary artery disease and multiple comorbidities. Whether process standardization using standard operating procedure (SOP) management and checklists improves HR-PCI is still unknown. METHODS AND RESULTS: This retrospective study analyzed procedural characteristics, in-hospital outcomes, and length of hospital stay in patients who received HR-PCI in a German heart center 12 months before the introduction of process standardization using SOP management-the SOP (-) group-and after the introduction of process standardization using SOP management-the SOP (+) group. A total of 192 patients were included, with 77 patients in the SOP (-) group and 115 patients in the SOP (+) group. The mean age in the SOP (-) group was 72.0 ± 10.2 years and 81.8% were male; mean age in the SOP (+) group was 75.2 ± 10.4 years and 68.7% were male. Acute kidney events were significantly lower in the SOP (+) group than in the SOP (-) group (7.0% vs 10.4%; P=.04). Bleeding was the most common adverse event and significantly lower in the SOP (+) group than in the SOP (-) group (13.1% vs 31.2%, respectively; P<.01). There were trends toward shorter length of hospital stay in the SOP (+) group compared with the SOP (-) group (9.3 ± 6.4 days vs 10.9 ± 7.3 days, respectively; P=.10) and days of hospital stay in the intensive care unit (3.7 ± 4.0 days vs 4.7 ± 4.3 days; P=.07). SOP management was independently associated with shorter length of hospital stay in multivariate regression analysis. CONCLUSION: This retrospective study shows significantly better quality of care measures after the introduction of process standardization techniques using SOP management in HRPCIs, with a lower risk of adverse outcomes and shorter length of hospital stay.
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Enfermedad de la Arteria Coronaria , Intervención Coronaria Percutánea , Anciano , Anciano de 80 o más Años , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/cirugía , Femenino , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Intervención Coronaria Percutánea/efectos adversos , Estándares de Referencia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Aberrant glucose homeostasis is the most common metabolic disturbance affecting one in ten adults worldwide. Prediabetic hyperglycemia due to dysfunctional interactions between different human tissues, including pancreas and liver, constitutes the largest risk factor for the development of type 2 diabetes. However, this early stage of metabolic disease has received relatively little attention. Microphysiological tissue models that emulate tissue crosstalk offer emerging opportunities to study metabolic interactions. Here, a novel modular multitissue organ-on-a-chip device is presented that allows for integrated and reciprocal communication between different 3D primary human tissue cultures. Precisely controlled heterologous perfusion of each tissue chamber is achieved through a microfluidic single "synthetic heart" pneumatic actuation unit connected to multiple tissue chambers via specific configuration of microchannel resistances. On-chip coculture experiments of organotypic primary human liver spheroids and intact primary human islets demonstrate insulin secretion and hepatic insulin response dynamics at physiological timescales upon glucose challenge. Integration of transcriptomic analyses with promoter motif activity data of 503 transcription factors reveals tissue-specific interacting molecular networks that underlie ß-cell stress in prediabetic hyperglycemia. Interestingly, liver and islet cultures show surprising counter-regulation of transcriptional programs, emphasizing the power of microphysiological coculture to elucidate the systems biology of metabolic crosstalk.
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Diabetes Mellitus Tipo 2 , Humanos , Microfluídica , Hígado , Páncreas , GlucosaRESUMEN
Background: The implantation depth (ID) is a critical condition for optimal hemodynamic and clinical outcomes in transcatheter aortic valve replacement (TAVR). The recently recommended cusp-overlap technique (COT) offers optimized fluoroscopic projections facilitating a precise ID. This single-center observational study aimed to investigate short-term clinical performance, safety, and efficacy outcomes in patients undergoing TAVR with self-expandable prostheses and application of COT in a real-world setting. Materials and methods: From September 2020 to April 2021, a total of 170 patients underwent TAVR with self-expandable devices and the application of COT, while 589 patients were treated from January 2016 to August 2020 with a conventional three-cusp coplanar view approach. The final ID and 30-day outcomes were compared after 1:1 propensity score matching, resulting in 150 patients in both cohorts. Results: The mean ID was significantly reduced in the COT cohort (-4.2 ± 2.7 vs. -4.9 ± 2.3 mm; p = 0.007) with an improvement of ID symmetry of less than 2 mm difference below the annular plane (47.3 vs. 57.3%; p = 0.083). The rate of new permanent pacemaker implantation (PPI) following TAVR was effectively reduced (8.0 vs. 16.8%; p = 0.028). While the fluoroscopy time decreased (18.4 ± 7.6 vs. 19.8 ± 7.6 min; p = 0.023), the dose area product increased in the COT group (4951 ± 3662 vs. 3875 ± 2775 Gy × cm2; p = 0.005). Patients implanted with COT had a shorter length of in-hospital stay (8.4 ± 4.0 vs. 10.3 ± 6.7 days; p = 0.007). Conclusion: Transcatheter aortic valve replacement using the cusp-overlap deployment technique is associated with an optimized implantation depth, leading to fewer permanent conduction disturbances. However, our in-depth analysis showed for the first time an increase of radiation dose due to extreme angulations of the gantry to obtain the cusp-overlap view.
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A 61-year-old male who underwent aortic valve replacement with an Inspiris Resilia® aortic bioprosthetic through an upper partial sternotomy due to severe aortic valve stenosis was presented 1 year later to our hospital suffering from dyspnoea and chest pain. The transthoracic echocardiography demonstrated moderate haemodynamic structural valve deterioration with a mean gradient of 29 mmHg and a valve area of 0.9 cm2. Due to relatively high-risk of reoperation, valve-in-valve transcatheter aortic valve replacement with Sapien 3® 29 mm, followed by balloon valvuloplasty, was successfully performed. To the best of our knowledge, this is the first published case of valve-in-valve transcatheter aortic valve replacement into a degenerated Inspiris Resilia® aortic valve.
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Estenosis de la Válvula Aórtica , Valvuloplastia con Balón , Bioprótesis , Prótesis Valvulares Cardíacas , Reemplazo de la Válvula Aórtica Transcatéter , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/cirugía , Bioprótesis/efectos adversos , Prótesis Valvulares Cardíacas/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Diseño de Prótesis , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Resultado del TratamientoRESUMEN
Exact and reliable measurements of anatomical dimensions in pre-procedural multi-slice computed tomography (MSCT) scans are crucial for optimal valve sizing and clinical results of transcatheter aortic valve replacement (TAVR). This study aimed to investigate interrater reliability between routinely used workflows for pre-procedural analysis. MSCT scans of 329 patients scheduled for TAVR were analyzed using both a 3mensio and SECTRA IDS7 platform. The results were retrospectively compared using the intraclass correlation coefficient, revealing excellent correlation in the analysis of simple diameters and poor correlation in the assessment of more complex structures with impact on calculated valve size.
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The hepatic Na+-taurocholate cotransporting polypeptide NTCP/SLC10A1 is important for the uptake of bile salts and selected drugs. Its inhibition results in increased systemic bile salt concentrations. NTCP is also the entry receptor for the hepatitis B/D virus. We investigated interindividual hepatic SLC10A1/NTCP expression using various omics technologies. SLC10A1/NTCP mRNA expression/protein abundance was quantified in well-characterized 143 human livers by real-time PCR and LC-MS/MS-based targeted proteomics. Genome-wide SNP arrays and SLC10A1 next-generation sequencing were used for genomic analyses. SLC10A1 DNA methylation was assessed through MALDI-TOF MS. Transcriptomics and untargeted metabolomics (UHPLC-Q-TOF-MS) were correlated to identify NTCP-related metabolic pathways. SLC10A1 mRNA and NTCP protein levels varied 44-fold and 10.4-fold, respectively. Non-genetic factors (e.g., smoking, alcohol consumption) influenced significantly NTCP expression. Genetic variants in SLC10A1 or other genes do not explain expression variability which was validated in livers (n = 50) from The Cancer Genome Atlas. The identified two missense SLC10A1 variants did not impair transport function in transfectants. Specific CpG sites in SLC10A1 as well as single metabolic alterations and pathways (e.g., peroxisomal and bile acid synthesis) were significantly associated with expression. Inter-individual variability of NTCP expression is multifactorial with the contribution of clinical factors, DNA methylation, transcriptional regulation as well as hepatic metabolism, but not genetic variation.
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Transportadores de Anión Orgánico Sodio-Dependiente , Simportadores , Ácidos y Sales Biliares/metabolismo , Cromatografía Liquida , Virus de la Hepatitis B/genética , Virus de la Hepatitis Delta/genética , Humanos , Hígado/metabolismo , Transportadores de Anión Orgánico Sodio-Dependiente/biosíntesis , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Péptidos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Simportadores/biosíntesis , Simportadores/genética , Simportadores/metabolismo , Espectrometría de Masas en Tándem , Ácido Taurocólico/metabolismoRESUMEN
Due to shortages of medical resources during the Coronavirus Disease 2019 (COVID-19) pandemic, an allocation algorithm for Transcatheter Aortic Valve Replacement (TAVR) was established. We investigated the impact on patient selection and procedural results. In total, 456 TAVR patients before (pre-COVID-19 group) and 456 TAVR patients after (COVID-19 group) the implementation of our allocation algorithm were compared. Concerning patient characteristics, the COVID-19 group revealed a higher rate of cardiac decompensations/cardiogenic shocks (10.5% vs. 1.3%; p < 0.001), severe angina pectoris (Canadian Cardiovascular Society (CCS) II, III and IV: 18.7% vs. 11.8%; p = 0.004), troponin elevation (>14 ng/L: 84.9% vs. 77%; p = 0.003) and reduced left ventricular ejection fraction (LVEF) (<45%: 18.9% vs. 12%; p = 0.006). Referring to procedural characteristics, more predilatations (46.3% vs. 35.1%; p = 0.001) and a longer procedural time (80.2 min (+/−29.4) vs. 66.9 min (+/−17.5); p < 0.001) were observed. The success rate was evenly high; no differences in safety parameters were reported. Examining the utilization of hospital resources, the COVID-19 group showed a shorter in-hospital stay (8.4 days (+/−5.9) vs. 9.5 days (+/−9.33); p = 0.041) and fewer TAVR patients were treated per month (39 (+/−4.55) vs. 46.11 (+/−7.57); p = 0.03). Our allocation algorithm supported prioritization of sicker patients with similar efficient and safe TAVR procedures. In-hospital stay could be shortened.
RESUMEN
Background: Cardiac auscultation is a core clinical skill taught in medical school. Due to contact restrictions during the SARS-CoV-2 pandemic, interaction with patients was very limited. Therefore, a peer-to-peer virtual case-based auscultation course via video conference was established. Methods: A randomized controlled cross-over study was conducted to evaluate whether participation in a virtual auscultation course could improve heart auscultation skills in 3rd-year medical students. A total of sixty medical students were randomly assigned to either the experimental or control group after informed consent was obtained. Due to no-shows, 55 students participated. Depending on allocation, students attended three ninety-minute courses in intervals of one week in a different order: a virtual case-based auscultation course held via video chat, literature self-study, and an on-site course using a high-fidelity auscultation simulator (SAM II). The study's primary endpoint was the performance of the two groups at the simulator after participating in the virtual auscultation course or literature self-study. To evaluate their auscultation skills, students participated in five assessments using the same six pathologies: stenosis and regurgitation of the aortic and mitral valve, ventricular septal defect, and patent ductus arteriosus. Moreover, participants rated their satisfaction with each course and provided a self-assessment of competence. Results: Compared to literature self-study, participation in the virtual auscultation course led to a significantly improved description of heart murmurs at the auscultation simulator with regard to the presence in systole and diastole, low- and high-pitched sounds, and volume dynamics. There was no significant difference between the groups in diagnostic accuracy and identification of the point of maximal intensity. After the virtual course, students showed higher satisfaction rates and a higher increase in self-assessed competence compared to participants who engaged in literature self-study. Conclusions: For the first time, this study demonstrates that a case-based virtual auscultation course can improve aspects of cardiac auscultation skills on a simulator. This may facilitate the further acquisition of an essential clinical skill, even when contact restrictions will be lifted.
Asunto(s)
COVID-19 , Estudiantes de Medicina , COVID-19/epidemiología , Competencia Clínica , Estudios Cruzados , Auscultación Cardíaca , Humanos , Estudios Prospectivos , SARS-CoV-2RESUMEN
Aims: The medical need for screening of aortic valve stenosis (AS), which leads to timely and appropriate medical intervention, is rapidly increasing because of the high prevalence of AS in elderly population. This study aimed to establish a screening method using understandable artificial intelligence (AI) to detect severe AS based on heart sounds and to package the built AI into a smartphone application. Methods and results: In this diagnostic accuracy study, we developed multiple convolutional neural networks (CNNs) using a modified stratified five-fold cross-validation to detect severe AS in electronic heart sound data recorded at three auscultation locations. Clinical validation was performed with the developed smartphone application in an independent cohort (model establishment: n = 556, clinical validation: n = 132). Our ensemble technique integrating the heart sounds from multiple auscultation locations increased the detection accuracy of CNN model by compensating detection errors. The established smartphone application achieved a sensitivity, specificity, accuracy, and F1 value of 97.6% (41/42), 94.4% (85/90), 95.7% (126/132), and 0.93, respectively, which were higher compared with the consensus of cardiologists (81.0%, 93.3%, 89.4%, and 0.829, respectively), implying a good utility for severe AS screening. The Gradient-based Class Activation Map demonstrated that the built AIs could focus on specific heart sounds to differentiate the severity of AS. Conclusions: Our CNN model combining multiple auscultation locations and exported on smartphone application could efficiently identify severe AS based on heart sounds. The visual explanation of AI decisions for heart sounds was interpretable. These technologies may support medical training and remote consultations.