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Calmodulin (CaM) is a ubiquitous, small cytosolic calcium (Ca2+)-binding sensor that plays a vital role in many cellular processes by binding and regulating the activity of over 300 protein targets. In cardiac muscle, CaM modulates directly or indirectly the activity of several proteins that play a key role in excitation-contraction coupling (ECC), such as ryanodine receptor type 2 (RyR2), l-type Ca2+ (Cav1.2), sodium (NaV1.5) and potassium (KV7.1) channels. Many recent clinical and genetic studies have reported a series of CaM mutations in patients with life-threatening arrhythmogenic syndromes, such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). We recently showed that four arrhythmogenic CaM mutations (N98I, D132E, D134H, and Q136P) significantly reduce the binding of CaM to RyR2. Herein, we investigate in vivo functional effects of these CaM mutations on the normal zebrafish embryonic heart function by microinjecting complementary RNA corresponding to CaMN98I, CaMD132E, CaMD134H, and CaMQ136P mutants. Expression of CaMD132E and CaMD134H mutants results in significant reduction of the zebrafish heart rate, mimicking a severe form of human bradycardia, whereas expression of CaMQ136P results in an increased heart rate mimicking human ventricular tachycardia. Moreover, analysis of cardiac ventricular rhythm revealed that the CaMD132E and CaMN98I zebrafish groups display an irregular pattern of heart beating and increased amplitude in comparison to the control groups. Furthermore, circular dichroism spectroscopy experiments using recombinant CaM proteins reveals a decreased structural stability of the four mutants compared to the wild-type CaM protein in the presence of Ca2+. Finally, Ca2+-binding studies indicates that all CaM mutations display reduced CaM Ca2+-binding affinities, with CaMD132E exhibiting the most prominent change. Our data suggest that CaM mutations can trigger different arrhythmogenic phenotypes through multiple and complex molecular mechanisms.
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Arritmias Cardíacas , Calmodulina , Peixe-Zebra , Animais , Calmodulina/metabolismo , Calmodulina/genética , Arritmias Cardíacas/genética , Arritmias Cardíacas/metabolismo , Mutação , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Humanos , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Mutação de Sentido Incorreto , Taquicardia Ventricular/genética , Taquicardia Ventricular/metabolismo , Cálcio/metabolismoRESUMO
OBJECTIVE: Otitis externa is a common condition managed by junior doctor-led ENT clinics in secondary/tertiary care, but no national guidelines exist for presentations in these settings. The aim of this study was to implement a treatment algorithm to support junior doctors and improve otitis externa management. METHODS: Baseline data were retrospectively collected for 16 weeks. A standardised otitis externa treatment algorithm was then implemented, and 16 weeks of data prospectively gathered. A second improvement cycle was completed thereafter focusing on topical antibiotics and water precaution advice. RESULTS: Overall, 202 cases of otitis externa managed between November 2021 to October 2022 were reviewed. Following the interventions, topical antibiotic prescribing improved (p = 0.01) as well as the provision of water precaution advice (p < 0.01). Junior doctors trended towards reviewing patients more frequently but required less senior support. CONCLUSION: Our treatment algorithm empowers junior doctors to become more independent in their management of otitis externa and improves overall otitis externa treatment.
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BACKGROUND: Type 2 diabetes (T2D) is a critical healthcare challenge and priority in Qatar which is listed amongst the top 10 countries in the world, with its prevalence presently at 17% double the global average. MicroRNAs (miRNAs) are implicated in the pathogenesis of (T2D) and long-term microvascular complications including diabetic retinopathy (DR). METHODS: In this study, a T2D cohort that accurately matches the characteristics of the general population was employed to find microRNA (miRNA) signatures that are correlated with glycemic and ß cell function measurements. Targeted miRNA profiling was performed in (471) T2D individuals with or without DR and (491) (non-diabetic) healthy controls from the Qatar Biobank. Discovery analysis identified 20 differentially expressed miRNAs in T2D compared to controls, of which miR-223-3p was significantly upregulated (fold change:5.16, p = 3.6e-02) and positively correlated with glucose and hemoglobin A1c (HbA1c) levels (p-value = 9.88e-04 and 1.64e-05, respectively), but did not show any significant associations with insulin or C-peptide. Accordingly, we performed functional validation using a miR-223-3p mimic (overexpression) under control and hyperglycemia-induced conditions in a zebrafish model. RESULTS: Over-expression of miR-223-3p alone was associated with significantly higher glucose (42.7 mg/dL, n = 75 vs 38.7 mg/dL, n = 75, p = 0.02) and degenerated retinal vasculature, and altered retinal morphology involving changes in the ganglion cell layer and inner and outer nuclear layers. Assessment of retinal angiogenesis revealed significant upregulation in the expression of vascular endothelial growth factor and its receptors, including kinase insert domain receptor. Further, the pancreatic markers, pancreatic and duodenal homeobox 1, and the insulin gene expressions were upregulated in the miR-223-3p group. CONCLUSION: Our zebrafish model validates a novel correlation between miR-223-3p and DR development. Targeting miR-223-3p in T2D patients may serve as a promising therapeutic strategy to control DR in at-risk individuals.
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Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Hiperglicemia , MicroRNAs , Humanos , Animais , Controle Glicêmico , Peixe-Zebra , Fator A de Crescimento do Endotélio Vascular , Insulina , GlucoseRESUMO
Diabetic nephropathy (DN) is one of the most established microvascular complications of diabetes and a key cause of end-stage renal disease. It is well established that gene susceptibility to DN plays a critical role in disease pathophysiology. Therefore, many genetic studies have been performed to categorize candidate genes in prominent diabetic cohorts, aiming to investigate DN pathogenesis and etiology. In this study, we performed a meta-analysis on the expression profiles of GSE1009, GSE30122, GSE96804, GSE99340, GSE104948, GSE104954, and GSE111154 to identify critical transcriptional factors associated with DN progression. The analysis was conducted for all individual datasets for each kidney tissue (glomerulus, tubules, and kidney cortex). We identified distinct clusters of susceptibility genes that were dysregulated in a renal compartment-specific pattern. Further, we recognized a small but a closely connected set of these susceptibility genes enriched for podocyte differentiation, several of which were characterized as genes encoding critical transcriptional factors (TFs) involved in DN development and podocyte function. To validate the role of identified TFs in DN progression, we functionally validated the three main TFs (DACH1, LMX1B, and WT1) identified through differential gene expression and network analysis using the hyperglycemic zebrafish model. We report that hyperglycemia-induced altered gene expression of the key TF genes leads to morphological abnormalities in zebrafish glomeruli, pronephric tubules, proximal and distal ducts. This study demonstrated that altered expression of these TF genes could be associated with hyperglycemia-induced nephropathy and, thus, aids in understanding the molecular drivers, essential genes, and pathways that trigger DN initiation and development.
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Emerging gene therapy clinical trials test the correction of hemophilia A (HA) by replacing factor VIII (FVIII) in autologous hematopoietic stem cells (HSCs). Although it is known that platelets, monocyte/macrophages, and mesenchymal stromal cells can secrete transgenic FVIII, a systematic examination of blood lineages as extrahepatic sources of FVIII, to our knowledge, has not yet been performed. In this study, we sought to provide a comprehensive map of native and lentivirus-based transgenic FVIII production from HSC stage to mature blood cells, through a flow cytometry analysis. In addition, we generated a model of transient HA in zebrafish based on antisense RNA, to assess the corrective potential of the FVIII-transduced HSCs. We discovered that FVIII production begins at the CD34+ progenitor stage after cytokine stimulation in culture. Among all mature white blood cells, monocytes are the largest producers of native FVIII and can maintain protein overexpression during differentiation from HSCs when transduced by a FVIII lentiviral vector. Moreover, the addition of the HSC self-renewal agonist UM171 to CD34+ cells during transduction expanded a subpopulation of CD14+/CD31+ monocytes with excellent ability to carry the FVIII transgene, allowing the correction of HA phenotype in zebrafish. Finally, the HA zebrafish model showed that f8 RNA is predominantly localized in the hematopoietic system at the larval stage, which indicates a potential contributory role of FVIII in hematopoiesis that warrants further investigation. We believe that this study may be of broad interest to hematologists and researchers striving to advance knowledge and permanent treatments for patients with HA.
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Hemofilia A , Hemostáticos , Animais , Fator VIII/genética , Células-Tronco Hematopoéticas/metabolismo , Hemofilia A/terapia , Monócitos/metabolismo , Peixe-Zebra/metabolismo , HumanosRESUMO
Variants in cardiac myosin-binding protein C (cMyBP-C) are the leading cause of inherited hypertrophic cardiomyopathy (HCM), demonstrating the key role that cMyBP-C plays in the heart's contractile machinery. To investigate the c-MYBPC3 HCM-related cardiac impairment, we generated a zebrafish mypbc3-knockout model. These knockout zebrafish displayed significant morphological heart alterations related to a significant decrease in ventricular and atrial diameters at systolic and diastolic states at the larval stages. Immunofluorescence staining revealed significant hyperplasia in the mutant's total cardiac and ventricular cardiomyocytes. Although cardiac contractility was similar to the wild-type control, the ejection fraction was significantly increased in the mypbc3 mutants. At later stages of larval development, the mutants demonstrated an early cardiac phenotype of myocardium remodeling, concurrent cardiomyocyte hyperplasia, and increased ejection fraction as critical processes in HCM initiation to counteract the increased ventricular myocardial wall stress. The examination of zebrafish adults showed a thickened ventricular cardiac wall with reduced heart rate, swimming speed, and endurance ability in both the mypbc3 heterozygous and homozygous groups. Furthermore, heart transcriptome profiling showed a significant downregulation of the actin-filament-based process, indicating an impaired actin cytoskeleton organization as the main dysregulating factor associated with the early ventricular cardiac hypertrophy in the zebrafish mypbc3 HCM model.
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Cardiomiopatia Hipertrófica , Peixe-Zebra , Actinas/genética , Actinas/metabolismo , Animais , Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Hiperplasia/metabolismo , Mutação , Miócitos Cardíacos/metabolismo , Transcriptoma , Peixe-Zebra/genética , Peixe-Zebra/metabolismoRESUMO
Hereditary hearing loss (HHL) is a common genetic disorder accounting for at least 60% of pre-lingual deafness in children, of which 70% is inherited in an autosomal recessive pattern. The long tradition of consanguinity among the Qatari population has increased the prevalence of HHL, which negatively impacts the quality of life. Here, we functionally validated the pathogenicity of the c.178G>C, p.E60Q mutation in the MYO6 gene, which was detected previously in a Qatari HHL family, using cellular and animal models. In vitro analysis was conducted in HeLa cells transiently transfected with plasmids carrying MYO6WT or MYO6p.E60Q, and a zebrafish model was generated to characterize the in vivo phenotype. Cells transfected with MYO6WT showed higher expression of MYO6 in the plasma membrane and increased ATPase activity. Modeling the human MYO6 variants in zebrafish resulted in severe otic defects. At 72 h post-injection, MYO6p.E60Q embryos demonstrated alterations in the sizes of the saccule and utricle. Additionally, zebrafish with MYO6p.E60Q displayed super-coiled and bent hair bundles in otic hair cells when compared to control and MYO6WT embryos. In conclusion, our cellular and animal models add support to the in silico prediction that the p.E60Q missense variant is pathogenic and damaging to the protein. Since the c.178G>C MYO6 variant has a 0.5% allele frequency in the Qatari population, about 400 times higher than in other populations, it could contribute to explaining the high prevalence of hearing impairment in Qatar.
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Surdez , Perda Auditiva Neurossensorial , Perda Auditiva , Animais , Surdez/genética , Células HeLa , Perda Auditiva/genética , Perda Auditiva Neurossensorial/genética , Humanos , Mutação , Cadeias Pesadas de Miosina/genética , Qualidade de Vida , Peixe-Zebra/genéticaRESUMO
In order to report clinically actionable incidental findings in genetic testing, the American College of Medical Genetics and Genomics (ACMG) recommended the evaluation of variants in 59 genes associated with highly penetrant mutations. However, there is a lack of epidemiological data on medically actionable rare variants in these genes in Arab populations. We used whole genome sequencing data from 6045 participants from the Qatar Genome Programme and integrated it with phenotypic data collected by the Qatar Biobank. We identified novel putative pathogenic variants in the 59 ACMG genes by filtering previously unrecorded variants based on computational prediction of pathogenicity, variant rarity and segregation evidence. We assessed the phenotypic associations of candidate variants in genes linked to cardiovascular diseases. Finally, we used a zebrafish knockdown and synthetic human mRNA co-injection assay to functionally characterize two of these novel variants. We assessed the zebrafish cardiac function in terms of heart rate, rhythm and hemodynamics, as well as the heart structure. We identified 52 492 novel variants, which have not been reported in global and disease-specific databases. A total of 74 novel variants were selected with potentially pathogenic effect. We prioritized two novel cardiovascular variants, DSP c.1841A > G (p.Asp614Gly) and LMNA c.326 T > G (p.Val109Gly) for functional characterization. Our results showed that both variants resulted in abnormal zebrafish heart rate, rhythm and structure. This study highlights medically actionable variants that are specific to the Middle Eastern Qatari population.
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Desmoplaquinas/genética , Achados Incidentais , Lamina Tipo A , Animais , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Lamina Tipo A/genética , Catar , Peixe-Zebra/genéticaRESUMO
Transcatheter aortic valve replacement (TAVR) offers a novel treatment option for patients with severe symptomatic aortic valve stenosis, particularly for patients who are unsuitable candidates for surgical intervention. However, high therapeutical costs, socio-economic considerations, and numerous comorbidities make it necessary to target and allocate available resources efficiently. In the present study, we aimed to identify risk factors associated with futile treatment following transfemoral (TF) and transapical (TA) TAVR. Five hundred and thirty-two consecutive patients (82 ± 9 years, female 63%) who underwent TAVR between June 2009 and December 2016 at the Vienna Heart Center Hietzing were retrospectively analyzed to identify predictors of futility, defined as all-cause mortality at one year following the procedure for the overall patient cohort, as well as the TF and TA cohort. Out of 532 patients, 91 (17%) did not survive the first year after TAVR. A multivariate logistic model identified cerebrovascular disease, home oxygen dependency, wheelchair dependency, periinterventional myocardial infarction, and postinterventional renal replacement therapy as the factors independently associated with an increased one-year mortality. Our findings underscore the significance of a precise preinterventional evaluation, as well as illustrating the subtle differences in baseline characteristics in the TF and TA cohort and their impact on one-year mortality.
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Transcatheter aortic valve replacement (TAVR) has rapidly become a viable alternative to the conventional isolated surgical aortic valve replacement (iSAVR) for treating severe symptomatic aortic stenosis. However, data on younger patients is scarce and a gap exists between data-based recommendations and the clinical use of TAVR. In our study, we utilized a machine learning (ML) driven approach to model the complex decision-making process of Heart Teams when treating young patients with severe symptomatic aortic stenosis with either TAVR or iSAVR and to identify the relevant considerations. Out of the considered factors, the variables most prominently featured in our ML model were congestive heart failure, established risk assessment scores, previous cardiac surgeries, a reduced left ventricular ejection fraction and peripheral vascular disease. Our study demonstrates a viable application of ML-based approaches for studying and understanding complex clinical decision-making processes.
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Microinjection technique is one of the essential methodologies that are used widely in zebrafish research. Microinjection is utilized to perform genetic manipulations within the developing zebrafish model. Further, this technique is used to study a wide range of genetic diseases and gene of interest role in early developmental processes. Thus, quality control for microinjection is an essential factor to ensure experimental reproducibility and consistency. In this technical note, in vitro transcribed synthetic mRNA encoding green fluorescence protein (eGFP), and red fluorescent protein (m-cherry) as well as fluorescein and rhodamine fluorescent dyes were injected into a single-cell zebrafish embryo for volume quality control. Given the importance of having quality control system and methodology to yield similar genetic manipulation within the zebrafish embryo:â¢We aimed to establish the unified delivery of injected material into zebrafish one cell stage embryo.â¢We aimed to establish consistency of the injected volume into mineral oil droplets that will serve as a quality control parameter to conforms a quality control practice to ensure the reproducibility of the microinjection technique.â¢The calibration of microinjection droplet size resulted in the visualization of fluorescent protein and dyes in the zebrafish embryo with precise volumes of delivered materials under the control of needle opening, injection pressure and time.
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BACKGROUND: Younger patients with severe symptomatic aortic stenosis are a particularly challenging collective with regard to the choice of intervention. High-risk patients younger than 75 years of age are often eligible for both the transcatheter aortic valve replacement (TAVR) and the isolated surgical aortic valve replacement (iSAVR). Data on the outcomes of both interventions in this set of patients are scarce. METHODS: One hundred and forty-four propensity score-matched patients aged 75 years or less who underwent TAVR or iSAVR at the Hietzing Heart Center in Vienna, Austria, were included in the study. The mean age was 68.9 years (TAVR 68.7 vs. SAVR 67.6 years; p = 0.190) and the average EuroSCORE II was 5.4% (TAVR 4.3 [3.2%] vs. iSAVR 6.4 (4.3%); p = 0.194). RESULTS: Postprocedural adverse event data showed higher rates of newly acquired atrial fibrillation (6.9% vs. 19.4%; p = 0.049), prolonged ventilation (2.8% vs. 25.0%; p < 0.001) and multi-organ failure (0% vs. 6.9%) in the surgical cohort. The in-hospital and 30-day mortality was significantly higher for iSAVR (1.4% vs. 13.9%; p = 0.012; 12.5% vs. 2.8%; p = 0.009, respectively). The long-term survival (median follow-up 5.0 years (2.2-14.1 years)) of patients treated with the surgical approach was superior to that of patients undergoing TAVR (p < 0.001). CONCLUSION: Although the survival analysis revealed a higher in-hospital and 30-day survival rate for high-risk patients aged ≤75 years who underwent TAVR, iSAVR was associated with a significantly higher long-term survival rate.
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BACKGROUND: We compared the outcomes and adverse events of TAVI patients based on the discharge and long-term antiplatelet or anticoagulant treatment regimens (single antiplatelet [SAPT] vs. dual antiplatelet [DAPT] vs. anticoagulation [OAC] vs. no treatment [NT]). METHODS: The outcome of 532 consecutive patients treated with TAVI was evaluated. As the main study endpoint, the 1-year all-cause mortality was chosen to compare the different discharge treatment regimens and the 3-year all-cause mortality to compare the different long-term treatment regimens. The secondary endpoints were adverse events as defined by the Valve Academic Research Consortium-II. RESULTS: One-year survival after TAVI was highest amongst patients treated with DAPT compared to SAPT (P < .001) and OAC (P = .003), and patients under OAC demonstrated improved 1-year survival over patients treated with SAPT (P = .006). Furthermore, there was a strong trend towards improved 3-year survival for patients in the OAC cohort treated with non-vitamin K antagonists compared to vitamin K antagonists (N-VKAs vs. VKA; log-rank P = .056). CONCLUSION: The lower all-cause mortality for DAPT within the first year and N-VKAs over VKA within the first 3 years warrant considerable attention in further recommendations of antithrombotic and anticoagulation regimens after TAVI.
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Anticoagulantes/uso terapêutico , Estenose da Valva Aórtica/cirurgia , Terapia Antiplaquetária Dupla/métodos , Inibidores do Fator Xa/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Cuidados Pós-Operatórios/métodos , Substituição da Valva Aórtica Transcateter , Idoso , Idoso de 80 Anos ou mais , Aspirina/uso terapêutico , Áustria/epidemiologia , Clopidogrel/uso terapêutico , Feminino , Fibrinolíticos/uso terapêutico , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Masculino , Sistema de Registros , Taxa de Sobrevida , Vitamina K/antagonistas & inibidoresRESUMO
BACKGROUND: This study aimed to evaluate the differences in outcome arising from the use of semi-compliant (SCB) versus non-compliant balloon (NCB) systems for predilatation during self-expanding transcatheter aortic valve replacement (TAVR). METHODS: 251 TAVR procedures with the implantation of self-expanding valves after predilatation were analyzed. SCB systems were used in 166 and NCB systems in 85 patients. The primary endpoint was defined as device success, a composite endpoint comprising the absence of procedural mortality, correct valve positioning, adequate valve performance and the absence of more than a mild paravalvular leak. The secondary endpoints were chosen in accordance with the valve academic research consortium (VARC-2) endpoint definitions. RESULTS: No significant differences were observed with regard to procedural device success between the SCB- and NCB cohort (SCB: 142 [85.5%%] vs. NCB: 77 [90.6%]; P = .257). There was a notable difference between the rates of conversion to open surgery and the postdilatation rate, both of which were higher for the NCB group (SCB: 1 [0.6%] vs. NCB: 4 [5.1%]; P = .042; SCB: 30 [18.1%] vs. NCB: 34 [40%]; P < .001). In a multivariate logistic regression analysis, the use of semi-compliant balloon systems for predilatation was associated with a lower risk for postdilatation (OR: 0.296; 95% CI: 0.149-0.588) and conversion to open surgery (OR: 0.205; 95% CI: 0.085-0.493; P = .001) but not for device success. CONCLUSION: While the balloon compliance did not affect the procedural mortality, device success or the rate of paravalvular leakage, the use of semi-compliant balloons for predilatation during TAVR should be investigated in larger randomized trials in the light of the lower rates of postdilatation and conversion to open surgery compared to their non-compliant counterparts.
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Estenose da Valva Aórtica/cirurgia , Valvuloplastia com Balão/instrumentação , Mortalidade , Substituição da Valva Aórtica Transcateter/instrumentação , Injúria Renal Aguda/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Bloqueio Atrioventricular/epidemiologia , Valvuloplastia com Balão/métodos , Bloqueio de Ramo/epidemiologia , Causas de Morte , Conversão para Cirurgia Aberta/estatística & dados numéricos , Feminino , Humanos , Masculino , Complicações Pós-Operatórias/epidemiologia , Sistema de Registros , Substituição da Valva Aórtica Transcateter/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Arterial tortuosity is linked to a higher risk of adverse clinical events after transfemoral transcatheter aortic valve replacement (TF-TAVR). Currently, there are no assessment tools that can quantify this variable in three-dimensional space. This study investigated the impact of novel scoring methods of iliofemoral tortuosity on access and bleeding complications after TF-TAVR. METHODS: The main access vessel was assessed between the aortoiliacal and femoral bifurcation in preoperative multislice computed tomography scans of 240 consecutive patients undergoing TF-TAVR. Tortuosity was assessed by three methods: largest single angle, sum of all angles, and iliofemoral tortuosity (IFT) score [((true vessel length/ideal vessel length)-1)*100]. The primary study endpoint was a composite of access and bleeding complications. The secondary study endpoints were 30-day mortality and long-term survival. RESULTS: Among 240 patients, only the IFT score demonstrated a good positive correlation with the composite primary endpoint of access and bleeding complications (P = 0.031). A higher incidence of access and bleeding complications was found in patients with a higher IFT score (56 [36.8%] vs 17 [19.3%]; P = 0.003). In a multivariate logistic regression analysis, only the IFT score was a significant predictor of the primary endpoint (OR: 2.11; 95% CI: 1.09-4.05; P = 0.026). CONCLUSION: Vascular tortuosity is an underestimated risk factor during TF-TAVR. The IFT score is a valuable tool in risk stratification before TF-TAVR, predicting periprocedural access and bleeding complications.
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Aorta/diagnóstico por imagem , Artéria Femoral/diagnóstico por imagem , Artéria Ilíaca/diagnóstico por imagem , Complicações Intraoperatórias/epidemiologia , Hemorragia Pós-Operatória/epidemiologia , Substituição da Valva Aórtica Transcateter/métodos , Lesões do Sistema Vascular/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Dissecção Aórtica/epidemiologia , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Feminino , Humanos , Masculino , Tomografia Computadorizada MultidetectoresRESUMO
BACKGROUND: While transcatheter aortic valve replacement (TAVR) has revolutionized the treatment of aortic valve stenosis, wearable health-monitoring devices are gradually transforming digital patient care. OBJECTIVE: The aim of this study was to develop a simple, efficient, and economical method for preprocedural frailty assessment based on parameters measured by a wearable health-monitoring device. METHODS: In this prospective study, we analyzed data of 50 consecutive patients with mean (SD) age of 77.5 (5.1) years and a median (IQR) European system for cardiac operative risk evaluation (EuroSCORE) II of 3.3 (4.1) undergoing either transfemoral or transapical TAVR between 2017 and 2018. Every patient was fitted with a wrist-worn health-monitoring device (Garmin Vivosmart 3) for 1 week prior to the procedure. Twenty different parameters were measured, and threshold levels for the 3 most predictive categories (ie, step count, heart rate, and preprocedural stress) were calculated. Patients were assigned 1 point per category for exceeding the cut-off value and were then classified into 4 stages (no, borderline, moderate, and severe frailty). Furthermore, the FItness-tracker assisted Frailty-Assessment Score (FIFA score) was compared with the scores of the preprocedural gait speed category derived from the 6-minute walk test (GSC-6MWT) and the Edmonton Frail Scale classification (EFS-C). The primary study endpoint was hospital mortality. RESULTS: The overall preprocedural stress level (P=.02), minutes of high stress per day (P=.02), minutes of rest per day (P=.045), and daily heart rate maximum (P=.048) as single parameters were the strongest predictors of hospital mortality. When comparing the different frailty scores, the FIFA score demonstrated the greatest predictive power for hospital mortality (FIFA area under the curve [AUC] 0.844, CI 0.656-1.000; P=.048; GSC-6MWT AUC 0.671, CI 0.487-0.855; P=.42; EFS-C AUC 0.636, CI 0.254-1.000; P=.44). CONCLUSIONS: This proof-of-concept study demonstrates the strong predictive performance of the FIFA score compared to that of the conventional frailty assessments.
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Fragilidade , Substituição da Valva Aórtica Transcateter , Idoso , Fragilidade/diagnóstico , Humanos , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Resultado do TratamentoRESUMO
Recent studies have suggested that contrast medium (CM) volume is associated with acute kidney injury (AKI) after transcatheter aortic valve replacement (TAVR). However, in a high-risk elderly TAVR population, the prognostic value and ideal threshold of CM dosage for AKI is unclear. Data of 532 successive TAVR patients (age 81.1 ± 6.8 years, EuroSCORE II 4.8% ± 6.0%) were therefore retrospectively analyzed. Based on a recently published formula, the renal function (preprocedural serum creatinine: SCr) corrected ratio of CM and body weight (CM*SCr/BW) was calculated to determine the risk of postprocedural contrast-associated AKI. AKI occurred in 94 patients (18.3%) and significantly increased 1-year all-cause mortality (23.4% vs. 13.1%; p = 0.001). A significant correlation between AKI and 30-day as well as 1-year all-cause mortality was observed (p = 0.001; p = 0.007). However, no association between CM dosage or the CM*SCr/BW ratio with the occurrence of AKI was seen (p = 0.968; p = 0.442). In our all-comers, all-access cohort, we found no relationship between CM dosage, or the established risk ratio model and the occurrence of postprocedural AKI. Further research needs to be directed towards different pathophysiological causes and preventive measures as AKI impairs short- and long-term survival.
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Recessive mutations in Post-GPI attachment to proteins 3 (PGAP3) cause the rare neurological disorder hyperphosphatasia with mental retardation syndrome 4 type (HPMRS4). Here, we report a novel homozygous nonsense mutation in PGAP3 (c.265C>T-p.Gln89*), in a 3-year-old boy with unique novel clinical features. These include decreased intrauterine fetal movements, dysgenesis of the corpus callosum, olfactory bulb agenesis, dysmorphic features, cleft palate, left ear constriction, global developmental delay, and hypotonia. The zebrafish functional modeling of PGAP3 loss resulted in HPMRS4-like features, including structural brain abnormalities, dysmorphic cranial and facial features, hypotonia, and seizure-like behavior. Remarkably, morphants displayed defective neural tube formation during the early stages of nervous system development, affecting brain morphogenesis. The significant aberrant midbrain and hindbrain formation demonstrated by separation of the left and right tectal ventricles, defects in the cerebellar corpus, and caudal hindbrain formation disrupted oligodendrocytes expression leading to shorter motor neurons axons. Assessment of zebrafish neuromuscular responses revealed epileptic-like movements at early development, followed by seizure-like behavior, loss of touch response, and hypotonia, mimicking the clinical phenotype human patients. Altogether, we report a novel pathogenic PGAP3 variant associated with unique phenotypic hallmarks, which may be related to the gene's novel role in brain morphogenesis and neuronal wiring.
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Anormalidades Múltiplas/genética , Encéfalo/patologia , Hidrolases de Éster Carboxílico/efeitos adversos , Deficiência Intelectual/genética , Distúrbios do Metabolismo do Fósforo/genética , Anormalidades Múltiplas/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Deficiência Intelectual/metabolismo , Morfogênese , Distúrbios do Metabolismo do Fósforo/metabolismo , Receptores de Superfície Celular , Peixe-ZebraRESUMO
BACKGROUND: We investigated the impact of an elevated plasma volume status (PVS) in patients undergoing TAVI on early clinical safety and mortality and assessed the prognostic utility of PVS for outcome prediction. MATERIALS AND METHODS: We retrospectively calculated the PVS in 652 patients undergoing TAVI between 2009 and 2018 at two centres. They were then categorized into two groups depending on their preoperative PVS (PVS ≤-4; n = 257 vs PVS>-4; n = 379). Relative PVS was derived by subtracting calculated ideal (iPVS = c × weight) from actual plasma volume (aPVS = (1 - haematocrit) × (a + (b × weight in kg)). RESULTS: The need for renal replacement therapy (1 (0.4%) vs 17 (4.5%); P = .001), re-operation for noncardiac reasons (9 (3.5%) vs 32 (8.4%); P = .003), re-operation for bleeding (9 (3.5%) vs 27 (7.1%); P = .037) and major bleeding (14 (5.4%) vs 37 (9.8%); P = .033) were significantly higher in patients with a PVS>-4. The composite 30-day early safety endpoint (234 (91.1%) vs 314 (82.8%); P = .002) confirms that an increased preoperative PVS is associated with a worse overall outcome after TAVI. CONCLUSIONS: An elevated PVS (>-4) as a marker for congestion is associated with significantly worse outcome after TAVI and therefore should be incorporated in preprocedural risk stratification.
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Determining transmural mechanical properties in the heart provides a foundation to understand physiological and pathophysiological cardiac mechanics. Although work on mechanical characterisation has begun in isolated cells and permeabilised samples, the mechanical profile of living individual cardiac layers has not been examined. Myocardial slices are 300 µm-thin sections of heart tissue with preserved cellular stoichiometry, extracellular matrix, and structural architecture. This allows for cardiac mechanics assays in the context of an intact in vitro organotypic preparation. In slices obtained from the subendocardium, midmyocardium and subepicardium of rats, a distinct pattern in transmural contractility is found that is different from that observed in other models. Slices from the epicardium and midmyocardium had a higher active tension and passive tension than the endocardium upon stretch. Differences in total myocyte area coverage, and aspect ratio between layers underlined the functional readouts, while no differences were found in total sarcomeric protein and phosphoprotein between layers. Such intrinsic heterogeneity may orchestrate the normal pumping of the heart in the presence of transmural strain and sarcomere length gradients in the in vivo heart.