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Psychostimulants interacting with the dopamine transporter (DAT) can be used illicitly or for the treatment of specific neuropsychiatric disorders. However, they can also produce severe and persistent adverse events. Often, their pharmacological properties in vitro do not fully correlate to their pharmacological profile in vivo. Here, we investigated the pharmacological effects of enantiomers of pyrovalerone, α-pyrrolidinovalerophenone, and 3,4-methylenedioxypyrovalerone as compared to the traditional psychostimulants cocaine and methylphenidate, using a variety of in vitro, computational, and in vivo approaches. We found that in vitro drug-binding kinetics at DAT correlate with the time-course of in vivo psychostimulant action in mice. In particular, a slow dissociation (i.e., slow koff) of S-enantiomers of pyrovalerone analogs from DAT predicts their more persistent in vivo effects when compared to cocaine and methylphenidate. Overall, our findings highlight the critical importance of drug-binding kinetics at DAT for determining the in vivo profile of effects produced by psychostimulant drugs.
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Estimulantes del Sistema Nervioso Central , Cocaína , Metilfenidato , Ratones , Animales , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Dopamina/metabolismo , Estimulantes del Sistema Nervioso Central/farmacología , Cocaína/farmacología , Cocaína/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Metilfenidato/farmacologíaRESUMEN
Increasing extracellular levels of serotonin (5-HT) in the brain ameliorates symptoms of depression and anxiety-related disorders, e.g., social phobias and post-traumatic stress disorder. Recent evidence from preclinical and clinical studies established the therapeutic potential of drugs inducing the release of 5-HT via the 5-HT-transporter. Nevertheless, current 5-HT releasing compounds under clinical investigation carry the risk for abuse and deleterious side effects. Here, we demonstrate that S-enantiomers of certain ring-substituted cathinones show preference for the release of 5-HT ex vivo and in vivo, and exert 5-HT-associated effects in preclinical behavioral models. Importantly, the lead cathinone compounds (1) do not induce substantial dopamine release and (2) display reduced off-target activity at vesicular monoamine transporters and 5-HT2B-receptors, indicative of low abuse-liability and low potential for adverse events. Taken together, our findings identify these agents as lead compounds that may prove useful for the treatment of disorders where elevation of 5-HT has proven beneficial.
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Dopamina , Serotonina , Encéfalo , Proteínas PortadorasRESUMEN
Organic cation transporters 1-3 (OCT1-3, SLC22A1-3) and the plasma membrane monoamine transporter (PMAT, SLC29A4) play a major role in maintaining monoaminergic equilibrium in the central nervous system. With many psychoactive substances interacting with OCT1-3 and PMAT, a growing literature focuses on characterizing their properties via in vitro and in vivo studies. In vitro studies mainly aim at characterizing compounds as inhibitors or substrates of murine, rat, and human isoforms. The preponderance of studies has put emphasis on phenylalkylamine derivatives, but ketamine and opioids have also been investigated. Studies employing in vivo (knockout) models mostly concentrate on the interaction of psychoactive substances and OCT3, with an emphasis on stress and addiction, pharmacokinetics, and sensitization to psychoactive drugs. The results highlight the importance of OCT3 in the mechanism of action of psychoactive compounds. Concerning in vivo studies, a veritable research gap concerning OCT1, 2, and PMAT exists. This review provides an overview and summary of research conducted in this field of research.
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Proteínas de Transporte de Catión Orgánico , Transportador 1 de Catión Orgánico , Animales , Transporte Biológico , Cationes , Humanos , Ratones , Proteínas de Transporte de Catión Orgánico/metabolismo , RatasRESUMEN
Many psychoactive compounds have been shown to primarily interact with high-affinity and low-capacity solute carrier 6 (SLC6) monoamine transporters for norepinephrine (NET; norepinephrine transporter), dopamine (DAT; dopamine transporter) and serotonin (SERT; serotonin transporter). Previous studies indicate an overlap between the inhibitory capacities of substances at SLC6 and SLC22 human organic cation transporters (SLC22A1-3; hOCT1-3) and the human plasma membrane monoamine transporter (SLC29A4; hPMAT), which can be classified as high-capacity, low-affinity monoamine transporters. However, interactions between central nervous system active substances, the OCTs, and the functionally-related PMAT have largely been understudied. Herein, we report data from 17 psychoactive substances interacting with the SLC6 monoamine transporters, concerning their potential to interact with the human OCT isoforms and hPMAT by utilizing radiotracer-based in vitro uptake inhibition assays at stably expressing human embryonic kidney 293 cells (HEK293) cells. Many compounds inhibit substrate uptake by hOCT1 and hOCT2 in the low micromolar range, whereas only a few substances interact with hOCT3 and hPMAT. Interestingly, methylphenidate and ketamine selectively interact with hOCT1 or hOCT2, respectively. Additionally, 3,4-methylenedioxymethamphetamine (MDMA) is a potent inhibitor of hOCT1 and 2 and hPMAT. Enantiospecific differences of R- and S-α-pyrrolidinovalerophenone (R- and S-α-PVP) and R- and S-citalopram and the effects of aromatic substituents are explored. Our results highlight the significance of investigating drug interactions with hOCTs and hPMAT, due to their role in regulating monoamine concentrations and xenobiotic clearance.
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Proteínas de Transporte de Nucleósido Equilibrativas/metabolismo , Proteínas Transportadoras de GABA en la Membrana Plasmática/metabolismo , Factores de Transcripción de Octámeros/metabolismo , Transportador 1 de Catión Orgánico/metabolismo , Transportador 2 de Cátion Orgánico/metabolismo , Psicotrópicos/farmacología , 3,4-Metilenodioxianfetamina/análogos & derivados , 3,4-Metilenodioxianfetamina/farmacología , Línea Celular , Sistema Nervioso Central/efectos de los fármacos , Citalopram/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Células HEK293 , Humanos , Pirrolidinas/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/metabolismoRESUMEN
BACKGROUND: Patients requiring extraction of infected or dysfunctional cardiac implantable electronic devices (CIED) have high morbidity and mortality. The Micra™ leadless cardiac pacemaker (LCP) may be beneficial for patients requiring permanent pacemaker therapy after CIED extraction. METHODS: This study aimed to assess the feasibility, timing and outcomes of LCP implantation in patients who underwent CIED extraction due to infection or dysfunction. The local Micra™ LCP registry was reviewed for LCP implantations and CIED extractions. RESULTS: Micra™ LCP implantation was scheduled for 48 consecutive patients (21 women, 44%) undergoing CIED extraction for infection (n = 38, 79%) or dysfunction (n = 10, 21%), and feasible in 47 (98%). Complete CIED removal was feasible in 44 patients (92%) and in 37/38 patients with infected CIED (97%). Overall, 32 LCP (67%) were implanted in a single procedure: 3 (6%) before and 13 (27%) after CIED extraction. LCP were implanted in a single procedure in 24/38 patients (63%) with infected CIED and in 8/10 patients (80%) with dysfunctional CIED. The in-hospital mortality rate was 6% (n = 3), and the survival rates at 30 days, 90 days and 1 year were 94% (n = 45/48), 90% (n = 43/48), and 85% (n = 41/48), respectively. No recurrent LCP-related mortality or infections occurred during a median follow-up of 15 (interquartile range, 12-41) months. CONCLUSION: Two-thirds of LCPs could be implanted in a single procedure with CIED extraction; no recurrent infections were detected. Overall, Micra™ LCP implantation in patients requiring CIED extraction was feasible.
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The presynaptic serotonin transporter (SERT) clears extracellular serotonin following vesicular release to ensure temporal and spatial regulation of serotonergic signalling and neurotransmitter homeostasis. Prescription drugs used to treat neurobehavioral disorders, including depression, anxiety, and obsessive-compulsive disorder, trap SERT by blocking the transport cycle. In contrast, illicit drugs of abuse like amphetamines reverse SERT directionality, causing serotonin efflux. Both processes result in increased extracellular serotonin levels. By combining molecular dynamics simulations with biochemical experiments and using a homologous series of serotonin analogues, we uncovered the coupling mechanism between the substrate and the transporter, which triggers the uptake of serotonin. Free energy analysis showed that only scaffold-bound substrates could initiate SERT occlusion through attractive long-range electrostatic interactions acting on the bundle domain. The associated spatial requirements define substrate and inhibitor properties, enabling additional possibilities for rational drug design approaches.
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Proteínas de Transporte de Serotonina en la Membrana Plasmática , Serotonina , Humanos , Ligandos , Ansiedad , Trastornos de AnsiedadRESUMEN
OBJECTIVES: Despite the paucity of evidence verifying its efficacy and safety, traditional Chinese medicine (TCM) is expanding in popularity and political support. Decisions to include TCM diagnoses in the International Classification of Diseases 11th Revision and campaigns to integrate TCM into national healthcare systems have occurred while public perception and usage of TCM, especially in Europe, remains undetermined. Accordingly, this study investigates TCM's popularity, usage and perceived scientific support, as well as its relationship to homeopathy and vaccinations. DESIGN/SETTING: We performed a cross-sectional survey of the Austrian population. Participants were either recruited on the street (in-person) or online (web-link) via a popular Austrian newspaper. PARTICIPANTS: 1382 individuals completed our survey. The sample was poststratified according to data derived from Austria's Federal Statistical Office. OUTCOME MEASURES: Associations between sociodemographic factors, opinion towards TCM and usage of complementary medicine (CAM) were investigated using a Bayesian graphical model. RESULTS: Within our poststratified sample, TCM was broadly known (89.9% of women, 90.6% of men), with 58.9% of women and 39.5% of men using TCM between 2016 and 2019. Moreover, 66.4% of women and 49.7% of men agreed with TCM being supported by science. We found a positive relationship between perceived scientific support for TCM and trust in TCM-certified medical doctors (ρ=0.59, 95% CI 0.46 to 0.73). Moreover, perceived scientific support for TCM was negatively correlated with proclivity to get vaccinated (ρ=-0.26, 95% CI -0.43 to -0.08). Additionally, our network model yielded associations between TCM-related, homeopathy-related and vaccination-related variables. CONCLUSIONS: TCM is widely known within the Austrian general population and used by a substantial proportion. However, a disparity exists between the commonly held public perception that TCM is scientific and findings from evidence-based studies. Emphasis should be placed on supporting the distribution of unbiased, science-driven information.
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Medicina Tradicional China , Percepción , Masculino , Humanos , Femenino , Austria , Estudios Transversales , Teorema de BayesRESUMEN
BACKGROUND: The Ready-To-Go (R2G) Questionnaire is a tool for rapid assessment of health risks for travel consultation. This study aims to assess the utility of the R2G Questionnaire in identifying high-risk travellers and predicting health events and behaviour during travel in the TOURIST2 prospective cohort. METHODS: TOURIST2 data were used to calculate the R2G medical and travel risk scores and categorize each participant based on their risk. The TOURIST2 study enrolled 1000 participants from Switzerland's largest travel clinics between 2017 and 2019. Participants completed daily smartphone application surveys before, during and after travel on health events and behaviours. We used regression models to analyse incidence of overall health events and of similar health events grouped into health domains (e.g. respiratory, gastrointestinal, accident/injury). Incidence rate ratios (IRR) are displayed with 95% confidence intervals (95% CI). RESULTS: R2G high-risk travellers experienced significantly greater incidence of health events compared to lower-risk travellers (IRR = 1.27, 95% CI: 1.22-1.33). Both the medical and travel scores showed significant positive associations with incidence of health events during travel (IRR = 1.11, 95% CI: 1.07-1.16; IRR = 1.07, 95% CI: 1.03-1.12, respectively), with significant increases in all health domains except skin disorders. Medical and travel risk scores were associated with different patterns in behaviour. Travellers with chronic health conditions accessed medical care during travel more often (IRR = 1.16, 95% CI: 1.03-1.31), had greater difficulty in carrying out planned activities (IRR = -0.04, 95% CI: -0.05, -0.02), and rated their travel experience lower (IRR = -0.04, 95% CI: -0.06, -0.02). Travellers with increased travel-related risks due to planned travel itinerary had more frequent animal contact (IRR = 1.09, 95% CI: 1.01-1.18) and accidents/injuries (IRR = 1.28, 95% CI: 1.15-1.44). CONCLUSIONS: The R2G Questionnaire is a promising risk assessment tool that offers a timesaving and reliable means to identify high-risk travellers. Incorporated into travel medicine websites, it could serve as a pre-consultation triage to help travellers self-identify their risk level, direct them to the appropriate medical provider(s), and help practitioners in giving more tailored advice.
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Teléfono Inteligente , Viaje , Humanos , Estudios Prospectivos , Encuestas y Cuestionarios , Evaluación de Resultado en la Atención de SaludRESUMEN
Long-term control of SARS-CoV-2 requires effective vaccination strategies. This has been challenged by public mistrust and the spread of misinformation regarding vaccine safety. Better understanding and communication of the longer-term and comparative experiences of individuals in the general population following vaccination are required. In this population-based longitudinal study, we included 575 adults, randomly selected from all individuals presenting to a Swiss reference vaccination center, for receipt of BNT162b2, mRNA1273, or JNJ-78436735. We assessed the prevalence, onset, duration, and severity of self-reported adverse effects over 12 weeks following vaccination. We additionally evaluated participants' perceptions of vaccines, trust in public health authorities and pharmaceutical companies, and compliance with public health measures. Most participants reported at least one adverse effect within 12 weeks following vaccination. Adverse effects were mostly mild or moderate, resolved within three days, and rarely resulted in anaphylaxis or hospitalizations. Female sex, younger age, higher education, and receipt of mRNA-1273 were associated with reporting adverse effects. Compared to JNJ-78436735 recipients, a higher proportion of mRNA vaccine recipients agreed that vaccination is important, and trusted public health authorities. Our findings provide real-world estimates of the prevalence of adverse effects following SARS-CoV-2 vaccination and highlight the importance of transparent communication to ensure the success of current or future vaccination campaigns.
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Monoamine transporters are of great interest for their role in the physiological activity of the body and their link to mental and behavioural disorders. Currently, static well-plate assays or manual perfusion systems are used to characterize the interaction of psychostimulants, antidepressants and drugs of abuse with the transporters but still suffer from significant drawbacks caused by lack of automation, for example, low reproducibility, non-comparability of results. An automated microfluidic platform was developed to address the need for more standardized procedures for cell-based assays. An automated system was used to control and drive the simultaneous perfusion of 12 channels on a microfluidic chip, establishing a more standardized protocol to perform release assays to study monoamine transporter-mediated substrate efflux. D-Amphetamine, GBR12909 (norepinephrine transporter) and p-chloroamphetamine, paroxetine (serotonin transporter) were used as control compounds to validate the system. The platform was able to produce the expected releasing (D-Amphetamine, p-chloroamphetamine) or inhibiting (GBR12909, paroxetine) profiles for the two transporters. The reduction of manual operation and introduction of automated flow control enabled the implementation of stronger standardized protocols and the possibility of obtaining higher throughput by increasing parallelization.
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Microfluídica , p-Cloroanfetamina , Paroxetina , Reproducibilidad de los Resultados , Proteínas de Transporte de Membrana , Perfusión , DextroanfetaminaRESUMEN
Introduction: Previous analyses have reported the outcomes of transcatheter aortic valve replacement (TAVR) for patients with low-flow, low-gradient (LFLG) aortic stenosis (AS), without stratifying according to the route of access. Differences in mortality rates among access routes have been established for high-gradient (HG) patients and hypothesized to be even more pronounced in LFLG AS patients. This study aims to compare the outcomes of patients with LFLG or HG AS following transfemoral (TF) or transapical (TA) TAVR. Methods: A total of 910 patients, who underwent either TF or TA TAVR with a median follow-up of 2.22 (IQR: 1.22-4.03) years, were included in this multicenter cohort study. In total, 146 patients (16.04%) suffered from LFLG AS. The patients with HG and LFLG AS were stratified according to the route of access and compared statistically. Results: The operative mortality rates of patients with HG and LFLG were found to be comparable following TF access. The operative mortality rate was significantly increased for patients who underwent TA access [odds ratio (OR): 2.91 (1.54-5.48), p = 0.001] and patients with LFLG AS [OR: 2.27 (1.13-4.56), p = 0.02], which could be corroborated in a propensity score-matched subanalysis. The observed increase in the risk of operative mortality demonstrated an additive effect [OR for TA LFLG: 5.45 (2.35-12.62), p < 0.001]. LFLG patients who underwent TA access had significantly higher operative mortality rates (17.78%) compared with TF LFLG (3.96%, p = 0.016) and TA HG patients (6.36%, p = 0.024). Conclusions: HG patients experienced a twofold increase in operative mortality rates following TA compared with TF access, while LFLG patients had a fivefold increase in operative mortality rates. TA TAVR appears suboptimal for patients with LFLG AS. Prospective studies should be conducted to evaluate alternative options in cases where TF is not possible.
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Giant coronary artery aneurysms (GCAAs) are rare cardiovascular malformations that necessitate a multimodal, interdisciplinary diagnostic and individualized interventional approach. This report describes the case of a young, healthy patient with an idiopathic GCAA with pseudoaneurysmal protrusion into the right atrium that caused syncope, cardiac decompensation, and arrhythmia, which subsided postoperatively.
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Aneurisma Coronario , Vasos Coronarios , Humanos , Vasos Coronarios/cirugía , Aneurisma Coronario/diagnóstico , Aneurisma Coronario/diagnóstico por imagen , Atrios Cardíacos , Arritmias Cardíacas/etiologíaRESUMEN
Organic cation transporters (OCTs) are membrane proteins that take up monoamines, cationic drugs and xenobiotics. We previously reported novel missense mutations of organic cation transporter 3 (OCT3, SLC22A3), some with drastically impacted transport capabilities compared to wildtype. For some variants, this was due to ER retention and subsequent degradation of the misfolded transporter. For other transporter families, it was previously shown that treatment of misfolded variants with pharmacological and chemical chaperones could restore transport function to a certain degree. To investigate two potentially ER-bound, misfolded variants (D340G and R348W), we employed confocal and biochemical analyses. In addition, radiotracer uptake assays were conducted to assess whether pre-treatment with chaperones could restore transporter function. We show that pre-treatment of cells with the chemical chaperone 4-PBA (4-phenyl butyric acid) leads to increased membrane expression of misfolded variants and is associated with increased transport capacity of D340G (8-fold) and R348W (1.5 times) compared to untreated variants. We herein present proof of principle that folding-deficient SLC22 transporter variants, in particular those of OCT3, are amenable to rescue by chaperones. These findings need to be extended to other SLC22 members with corroborated disease associations.
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Mutación Missense , Transporte Biológico , Cationes , Factor 3 de Transcripción de Unión a Octámeros/metabolismoRESUMEN
[This corrects the article DOI: 10.3389/fphar.2020.00673.].
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NT-pro-BNP is produced in the cardiac atria and ventricles in response to increased wall stress. It may be a marker of both AF disease progression and co-morbidities that affect success after pulmonary vein isolation (PVI). This single-center retrospective study analyzed the association between pre-procedural NT-pro-BNP serum levels and the long-term outcome after a first-ever PVI in cryo-technique. Patients were followed by searching the hospital information system and conducting structured telephone interviews. Treatment failure was defined as any relapse of atrial fibrillation (AF) occurring 90 days after the index PVI at the earliest. Kaplan−Meier survival curves and Cox proportional hazards models were computed to assess the impact of NT-pro-BNP on AF recurrence. Following 374 patients over a median of 3.8 years (range: 0.25−9.4 years), baseline NT-pro-BNP was associated with the combined endpoint in univariate analysis (HR 1.04 per 100 pg/mL increase, 95% CI: 1.02−1.07, p < 0.001). Results were virtually unchanged in the multivariate model or if the data were log-transformed. Intraprocedural left atrial pressure correlated positively with log NT-pro-BNP. NT-pro-BNP was associated with AF relapse during a long-term follow-up after first-ever cryo-PVI in our cohort of patients with predominantly normal left ventricular function. This lab parameter is easy to obtain and has significant potential to guide treatment decisions.
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Organic cation transporters (OCTs) facilitate the translocation of catecholamines, drugs and xenobiotics across the plasma membrane in various tissues throughout the human body. OCT3 plays a key role in low-affinity, high-capacity uptake of monoamines in most tissues including heart, brain and liver. Its deregulation plays a role in diseases. Despite its importance, the structural basis of OCT3 function and its inhibition has remained enigmatic. Here we describe the cryo-EM structure of human OCT3 at 3.2 Å resolution. Structures of OCT3 bound to two inhibitors, corticosterone and decynium-22, define the ligand binding pocket and reveal common features of major facilitator transporter inhibitors. In addition, we relate the functional characteristics of an extensive collection of previously uncharacterized human genetic variants to structural features, thereby providing a basis for understanding the impact of OCT3 polymorphisms.
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Corticosterona , Proteínas de Transporte de Catión Orgánico , Humanos , Proteínas de Transporte de Catión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/metabolismo , Transporte Biológico , Corticosterona/farmacología , Catecolaminas , Cationes/metabolismo , Transportador 1 de Catión Orgánico/genética , Transportador 1 de Catión Orgánico/metabolismo , Transportador 2 de Cátion Orgánico/metabolismoRESUMEN
Despite recent advances in cancer immunotherapy, certain tumor types, such as Glioblastomas, are highly resistant due to their tumor microenvironment disabling the anti-tumor immune response. Here we show, by applying an in-silico multidimensional model integrating spatially resolved and single-cell gene expression data of 45,615 immune cells from 12 tumor samples, that a subset of Interleukin-10-releasing HMOX1+ myeloid cells, spatially localizing to mesenchymal-like tumor regions, drive T-cell exhaustion and thus contribute to the immunosuppressive tumor microenvironment. These findings are validated using a human ex-vivo neocortical glioblastoma model inoculated with patient derived peripheral T-cells to simulate the immune compartment. This model recapitulates the dysfunctional transformation of tumor infiltrating T-cells. Inhibition of the JAK/STAT pathway rescues T-cell functionality both in our model and in-vivo, providing further evidence of IL-10 release being an important driving force of tumor immune escape. Our results thus show that integrative modelling of single cell and spatial transcriptomics data is a valuable tool to interrogate the tumor immune microenvironment and might contribute to the development of successful immunotherapies.
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Neoplasias Encefálicas/inmunología , Glioblastoma/inmunología , Interleucina-10/metabolismo , Células Mieloides/metabolismo , Linfocitos T/inmunología , Adulto , Anciano , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Comunicación Celular/inmunología , Línea Celular Tumoral , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Voluntarios Sanos , Hemo-Oxigenasa 1/metabolismo , Humanos , Inmunoterapia/métodos , Inhibidores de las Cinasas Janus/farmacología , Inhibidores de las Cinasas Janus/uso terapéutico , Quinasas Janus/antagonistas & inhibidores , Quinasas Janus/metabolismo , Masculino , Persona de Mediana Edad , Neocórtex/citología , Neocórtex/inmunología , Neocórtex/patología , Cultivo Primario de Células , RNA-Seq , Factores de Transcripción STAT/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Análisis de la Célula Individual , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Técnicas de Cultivo de Tejidos , Escape del Tumor , Microambiente Tumoral/inmunologíaRESUMEN
The plasmalemmal norepinephrine transporter (NET) regulates cardiovascular sympathetic activity by clearing extracellular norepinephrine in the synaptic cleft. Here, we investigate the subunit stoichiometry and function of NET using single-molecule fluorescence microscopy and flux assays. In particular, we show the effect of phosphatidylinositol 4,5-bisphosphate (PIP2) on NET oligomerization and efflux. NET forms monomers (~60%) and dimers (~40%) at the plasma membrane. PIP2 depletion results in a decrease in the average oligomeric state and decreases NET-mediated substrate efflux while not affecting substrate uptake. Mutation of the putative PIP2 binding residues R121, K334, and R440 to alanines does not affect NET dimerization but results in decreased substrate efflux that is not altered upon PIP2 depletion; this indicates that PIP2 interactions with these residues affect NET-mediated efflux. A dysregulation of norepinephrine and PIP2 signaling have both been implicated in neuropsychiatric and cardiovascular diseases. This study provides evidence that PIP2 directly regulates NET organization and function.
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Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Fosfatidilinositoles , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/genética , Dimerización , Transporte Biológico , Fosfatos de Inositol , NorepinefrinaRESUMEN
Patients with symptomatic, drug-refractory atrial fibrillation (AF) are frequently treated with catheter ablation. Cryo-ablation has been established as an alternative to radiofrequency ablation but long-term outcome data are still limited. This study aimed at elucidating the influence of the left atrial volume index (LAVI), derived from cardiac computed tomography (cCT) data, on the long-term outcome of ablation-naïve AF patients, after their first cryo-ablation. 415 patients (nâ¯=â¯290 [69.90%] male, 60.00 [IQR: 53.00 to 68.00] years old) who underwent a cCT and subsequent cryo-ablation index procedure were included in this single centre retrospective data analysis. A composite end point was defined (AF on electrocardiogram and/or electric cardioversion and/or re-do). Patients were closely followed for a year and then contacted for long-term follow-up after a median of 53.00 months (IQR: 34.50 to 73.00). Statistical analyses of the outcome and predictors of AF recurrence were conducted. In 224 patients (53.98%) no evidence of AF recurrence could be found. LAVI differed significantly between the positive and adverse (AF recurrence) outcome group (49.96 vs 56.07 ml/m2, p < 0.001). Cox regression analyses revealed cCT LAVI (HR: 1.022, 95% CI: 1.013 to 1.031, p < 0.001), BMI (HR: 1.044, 95% CI: 1.005 to 1.084, p < 0.05) and the type of AF (HR: 1.838 for nonparoxysmal AF, 95% CI: 1.214 to 2.781, p < 0.01) to be effective predictors of AF recurrence. A prognostic cCT LAVI cut-off value of 51.99 ml/m2 was calculated and must be validated in future prospective studies. In conclusion, LAVI is an accurate, yet underutilized predictor of AF recurrence after pulmonary vein isolation with cryo-energy and scores for calculating AF recurrence or progression risks might underemphasize the importance of CT-derived LAVI as a predictive factor.