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Neuromodulation by means of vagus nerve stimulation (VNS) therapy, reduces seizure frequency and improves quality of life in subjects with drug-resistant epilepsy (DRE), yet its molecular mechanism remains unclear. This study investigates the impact of chronic VNS on lipid bioactive metabolites and fatty acids (FA) in the plasma and red blood cells of seven subjects with DRE. By measuring expression levels of peroxisome proliferator-activated receptor α (PPARα) and sirtuin1 (SIRT1) genes-key regulators in energy and lipid metabolism-and lipid profiles before and after various stages of VNS, this study identifies potential mechanisms by which VNS may reduce seizure frequency. Blood samples collected before VNS device implantation, after acute VNS stimulus, and following gradual intensity increments up to therapeutic levels revealed that VNS increases SIRT1 and PPARα expression and erythrocyte concentrations of PPARα ligands. Additionally, we observe reduced de novo lipogenesis biomarkers in erythrocytes, indicating that VNS may influence systemic lipid and energy metabolism. Our findings suggest that VNS could enhance neuronal function by modulating energy metabolism, thus potentially reducing seizure frequency in subjects with DRE. Future research targeting SIRT1 and PPARα may provide innovative therapeutic strategies for managing DRE. Plain Language Summary: The exact mechanism of VNS is still unknown. This study investigated the effects of VNS Therapy on energetic metabolism, suggesting possible novel biomarkers for DRE subjects and neuromodulation therapies.
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Epilepsia Refractaria , Estimulación del Nervio Vago , Humanos , Calidad de Vida , PPAR alfa , Sirtuina 1 , Epilepsia Refractaria/terapia , Convulsiones , Ácidos GrasosRESUMEN
OBJECTIVE: To evaluate the role of cyanoacrylate glue in reducing dislodgement of umbilical venous catheters (UVCs). STUDY DESIGN: This was a single-center, randomized, controlled, nonblinded trial. All infants requiring an UVC according to our local policy were included in the study. Infants with a UVC with a centrally located tip as verified by real-time ultrasound examination were eligible for the study. Primary outcome was the safety and efficacy of securement by cyanoacrylate glue plus cord-anchored suture (SG group) vs securement by suture alone (S group), as measured by reduction in dislodgment of the external tract of the catheter. Secondary outcomes were tip migration, catheter-related bloodstream infection, and catheter-related thrombosis. RESULTS: In the first 48 hours after UVC insertion, dislodgement was significantly higher in the S group than in the SG group (23.1% vs 1.5%; P < .001). The overall dislodgement rate was 24.6% in the S group vs 7.7% in the SG group (P = .016). No differences were found in catheter-related bloodstream infection and catheter-related thrombosis. The incidence of tip migration was similar in both groups (S group 12.2% vs SG group 11.7%). CONCLUSIONS: In our single-center study, cyanoacrylate glue was safe and effective for securement of UVCs, and particularly effective in decreasing early catheter dislodgments. TRIAL REGISTRATION: UMIN-CTR Clinical Trial; Registration number: R000045844.
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Infecciones Relacionadas con Catéteres , Cateterismo Venoso Central , Cateterismo Periférico , Sepsis , Trombosis , Enfermedades Vasculares , Lactante , Humanos , Cianoacrilatos/uso terapéutico , Catéteres , Venas , Venas UmbilicalesRESUMEN
Background: Vagal nerve stimulation (VNS) improves seizure frequency and quality of life in patients with drug-resistant epilepsy (DRE), although the exact mechanism is not fully understood. Previous studies have evaluated the effect of VNS on functional connectivity using the phase lag index (PLI), but none has analyzed its effect on EEG aperiodic parameters (offset and exponent), which are highly conserved and related to physiological functions. Objective: This study aimed to evaluate the effect of VNS on PLI and aperiodic parameters and infer whether these changes correlate with clinical responses in subjects with DRE. Materials and methods: PLI, exponent, and offset were derived for each epoch (and each frequency band for PLI), on scalp-derived 64-channel EEG traces of 10 subjects with DRE, recorded before and 1 year after VNS. PLI, exponent, and offset were compared before and after VNS for each patient on a global basis, individual scalp regions, and channels and separately in responders and non-responders. A correlation analysis was performed between global changes in PLI and aperiodic parameters and clinical response. Results: PLI (global and regional) decreased after VNS for gamma and delta bands and increased for an alpha band in responders, but it was not modified in non-responders. Aperiodic parameters after VNS showed an opposite trend in responders vs. non-responders: both were reduced in responders after VNS, but they were increased in non-responders. Changes in aperiodic parameters correlated with the clinical response. Conclusion: This study explored the action of VNS therapy from a new perspective and identified EEG aperiodic parameters as a new and promising method to analyze the efficacy of neuromodulation.
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A 70-year-old male patient was admitted to the emergency room in cardiac arrest. The patient was resuscitated and then referred to our cardiac surgery department, where he was diagnosed with suspected effusive constrictive pericarditis. A failed trial of TEE-guided pericardiocentesis led to the decision of surgical intervention. Sternotomy was performed and revealed pericardial thickening and very dense adhesions involving the pericardium and both pleurae, suggesting a neoplastic disease. An extensive pericardiectomy and bilateral pleural decortication were performed. After surgery, the patient improved significantly and was discharged from the intensive care unit 24 h later. Pericardial thickening, dense adhesions, the amount and color of pericardial fluid and the aspect of epicardial tissue increased our suspicion of neoplastic disease. Histological samples were sent to be analyzed immediately; a few days later, they were unexpectedly negative for any neoplastic disease but showed a group-B-hemolytic Streptococcus agalactiae infection, which causes pericarditis in extremely rare cases. Postoperatively, the patient, under intravenous antibiotic and anti-inflammatory therapy, remained asymptomatic and was discharged ten days after the surgery. At the three-month follow-up, transthoracic echocardiography showed a normal right and left ventricular function with no pericardial effusion.
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Derrame Pericárdico , Pericarditis Constrictiva , Infecciones Estreptocócicas , Anciano , Humanos , Masculino , Derrame Pericárdico/microbiología , Derrame Pericárdico/cirugía , Pericardiectomía , Pericardiocentesis , Pericarditis Constrictiva/cirugía , Infecciones Estreptocócicas/complicaciones , Streptococcus agalactiaeRESUMEN
We report the case of a 62-year-old male who underwent urgent cardiac surgery due to the incidental finding of a huge and asymptomatic coronary button pseudoaneurysm at an 18-month outpatients clinic follow-up requiring a very complex preoperative planning.
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Aneurisma Falso , Procedimientos Quirúrgicos Cardíacos , Aneurisma Falso/diagnóstico por imagen , Aneurisma Falso/etiología , Aneurisma Falso/cirugía , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Humanos , Hallazgos Incidentales , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugíaRESUMEN
BACKGROUND: The incidence of coronary artery disease (CAD) is high in patients with an aortic aneurysm but preoperative routine coronary angiography and preventive coronary revascularization are not recommended to reduce cardiac events in patients with severe CAD. AIM: This study evaluated the safeness and efficacy of preventive percutaneous coronary intervention (PCI) in patients with severe CAD scheduled for endovascular aneurysm repair (EVAR). METHODS: All patients with descending thoracic aneurysm (DTA) or abdominal aortic aneurysm (AAA) scheduled for EVAR underwent preliminary coronary angiography. Based on coronary angiography results, 917 patients (40.7%) had significant CAD and were treated by percutaneous coronary intervention (PCI; CAD group) and 1337 patients (59.3%) were without or with mild/moderate CAD and were considered as controls (no-CAD group). To evaluate the safeness and efficacy of preventive PCI in patients with severe CAD undergoing EVAR, groups were compared for hospital and 12-month cardiac adverse events. RESULTS: CAD was present in 1210 patients (53.6%): significant in 917 patients (38%) and mild to moderate in 293 patients (5.3%). Hospital and 12-month cardiac events occurred in 15 (1.6%) and 13 (1.4%) CAD group patients and in 9 (0.7%) and 8 (0.4%) no-CAD group patients (p = .05 and p = .08), respectively. Hospital and 12-month cardiac deaths occurred in 3 (0.3%) and 2 (0.2%) CAD group patients and in 3 (0.2%) and 2 (0.2%) no-CAD group patients (p = .9 and p = .9), respectively. CONCLUSION: The strategy to treat severe CAD preoperatively by PCI and early subsequent EVAR brings a similar outcome to that in patients without or with mild/moderate CAD.
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Aneurisma de la Aorta Abdominal , Implantación de Prótesis Vascular , Enfermedad de la Arteria Coronaria , Procedimientos Endovasculares , Intervención Coronaria Percutánea , Aneurisma de la Aorta Abdominal/cirugía , Enfermedad de la Arteria Coronaria/cirugía , Humanos , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
The umbilical venous catheter (UVC) is one of the most commonly used central lines in neonates. It can be easily inserted soon after birth providing stable intravenous access in infants requiring advanced resuscitation in the delivery room or needing medications, fluids, and parenteral nutrition during the 1st days of life. Resident training is crucial for UVC placement. The use of simulators allows trainees to gain practical experience and confidence in performing the procedure without risks for patients. UVCs are easy to insert, however when the procedure is performed without the use of ultrasound, there is a quite high risk, up to 40%, of non-central position. Ultrasound-guided UVC tip location is a simple and learnable technique and therefore should be widespread among all physicians. The feasibility of targeted training on the use of point-of-care ultrasound (POCUS) for UVC placement in the neonatal intensive care unit (NICU) among neonatal medical staff has been demonstrated. Conversely, UVC-related complications are very common and can sometimes be life-threatening. Despite UVCs being used by neonatologists for over 60 years, there are still no standard guidelines for assessment or monitoring of tip location, securement, management, or dwell time. This review article is an overview of the current knowledge and evidence available in the literature about UVCs. Our aim is to provide precise and updated recommendations on the use of this central line.
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OBJECTIVE: To retrospectively verify whether the positioning of the umbilical venous catheter (UVC) in the delivery room (DR) and the early start of the preheated infusion of 10% glucose solution conditioned temperature and glycemia values of ELBW neonates in the first hours of life. METHODS: Neonates (N = 137) were divided into two groups on the basis of timing of positioning of the UVC. In Group I the UVC was placed in DR, while in Group II after Neonatal Intensive Care Unit (NICU) admission. Data were assessed in different times: body temperature at neonatal admission to NICU (T1); after 2 hours (T2); then, every 2 hours until normothermia; glycemia value at NICU admission, every 1-2 hours in the first 12 hours, every 4 hours from 12 to 24 hours, and every 6-12 hours until normalization. Time slot childbirth was also detected since only in the morning shift there was a dedicated resuscitation team always present in DR, while during the afternoon and night it was available on-call. Preventive measures to limit heat dispersion were adopted in both Groups. RESULTS: In Group I respect to Group II, both at T1 and T2: (a) the rate of normothermic neonates was higher and (b) the rate of neonates with moderate hypothermia was lower. The hourly temperature increase was similar between the groups and the time needed to reach normothermia was significantly lower in Group I than in Group II. Glycemic values at T1 were lower in Group II. In Group II, after UVC positioning and glucose solution administration, the 42.2% of infants immediately brought glycemia back to normal, while the 57.8% needed specific treatment. The majority of newborns of Group I was born during the morning shift. CONCLUSIONS: The early UVC placement by a dedicated interdisciplinary team is a relevant intervention to carry out during the "Golden minutes" to improve the ELBW stabilization soon after birth.
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Hipotermia , Recien Nacido con Peso al Nacer Extremadamente Bajo , Salas de Parto , Femenino , Humanos , Hipotermia/prevención & control , Lactante , Recién Nacido , Recién Nacido de muy Bajo Peso , Unidades de Cuidado Intensivo Neonatal , Embarazo , Estudios RetrospectivosRESUMEN
BACKGROUND: Pregnancy usually represents a risk factor for aortic dissection or thrombotic events, but therapeutic options are very scarce because the foetus limits the common approaches especially in the early stages of pregnancy. CASE PRESENTATION: We present a challenging case of a young woman in her 16th week of gestation with an history of multiple abortions associated with autoimmune thrombophilia. A strictly designed perioperative management protocol was required to remove a huge right endoventricular mass, due to her decision to not terminate the pregnancy. CONCLUSIONS: Nowadays the mother, completely healthy, gived birth to her baby so it demonstrates how cardiac surgery, even in complicated circumstances, can be feasible during pregnancy through a multidisciplinary approach.
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Disección Aórtica , Procedimientos Quirúrgicos Cardíacos , Complicaciones Cardiovasculares del Embarazo , Puente Cardiopulmonar , Femenino , Humanos , Embarazo , Factores de RiesgoRESUMEN
Objective: To evaluate the course of fecal calprotectin (FC) in very preterm infants over the first 15 days of life in relation to the type of milk diet. Methods: This study was part of a randomized controlled trial comparing two different ways of integrating the own mother's milk (OMM) for the evaluation of feeding tolerance in very preterm infants. In infants with gestational age of ≤ 32 weeks randomized to receive preterm formula (PF group) or pasteurized donor human milk (PDHM group) as a supplement to the OMM insufficient or unavailable, FC level was planned to be measured at the first meconium passage and at days 8 and 15 of life (T0, T1, and T2, respectively). Results: FC data were available for all the 70 infants randomized, 35 in the PF group, and 35 in the PDHM group. The mean FC levels were similar in the two study groups at T0 and T1, whereas they were significantly higher in the PF group than the PDHM group at T2. FC values decreased over the first week of life in both groups and significantly increased over the second week of life only in the PF group. Conclusions: Our study demonstrates a significant increase in FC levels when PF is used as a supplement to the OMM compared to the use of PDHM. Further studies are needed to establish if the higher FC levels in infants receiving PF are the expression of a normal immunological maturation rather than an initial inflammatory process.
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COVID-19 pandemic triggered in many patients the fear to go to the emergency rooms in order to avoid a possible infection. This phenomenon caused a significant reduction in acute coronary syndrome-related interventional procedures with a subsequent increase in critical hospitalizations and post-infarction mechanical complications. A case series of cardiac ruptures during the COVID-19 lockdown and the surgical treatment of a huge post-ischemic cardiac pseudoaneurysm complicated by a "contained" free wall rupture are presented.
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Infarto del Miocardio , Aneurisma Falso/diagnóstico , Aneurisma Falso/etiología , Aneurisma Falso/terapia , COVID-19 , Infecciones por Coronavirus , Femenino , Humanos , Italia , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/terapia , Pandemias , Neumonía ViralRESUMEN
Kpkt is a yeast killer toxin, naturally produced by Tetrapisispora phaffii, with possible applications in winemaking due to its antimicrobial activity on wine-related yeasts including Kloeckera/Hanseniaspora, Saccharomycodes and Zygosaccharomyces. Here, Kpkt coding gene was expressed in Komagataella phaffii (formerly Pichia pastoris) and the bioreactor production of the recombinant toxin (rKpkt) was obtained. Moreover, to produce a ready-to-use preparation of rKpkt, the cell-free supernatant of the K. phaffii recombinant killer clone was 80-fold concentrated and lyophilized. The resulting preparation could be easily solubilized in sterile distilled water and maintained its killer activity for up to six months at 4 °C. When applied to grape must, it exerted an extensive killer activity on wild wine-related yeasts while proving compatible with the fermentative activity of actively growing Saccharomyces cerevisiae starter strains. Moreover, it displayed a strong microbicidal effect on a variety of bacterial species including lactic acid bacteria and food-borne pathogens. On the contrary it showed no lethal effect on filamentous fungi and on Ceratitis capitata and Musca domestica, two insect species that may serve as non-mammalian model for biomedical research. Based on these results, bioreactor production and lyophilization represent an interesting option for the exploitation of this killer toxin that, due to its spectrum of action, may find application in the control of microbial contaminations in the wine and food industries.
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Factores Asesinos de Levadura/farmacología , Vino/microbiología , Antiinfecciosos/metabolismo , Antiinfecciosos/farmacología , Reactores Biológicos/microbiología , Fermentación , Industria de Alimentos , Microbiología de Alimentos , Liofilización , Factores Asesinos de Levadura/biosíntesis , Viabilidad Microbiana , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/farmacología , Levaduras/efectos de los fármacosRESUMEN
BACKGROUND: Persistent right umbilical vein (PRUV) is one of the most common prenatally detected venous anomaly. In the intrahepatic variant (I-PRUV) the right umbilical vein fuses with right portal vein and through the ductus venous drains into inferior vena cava, while in the uncommon extrahepatic variant (E-PRUV), the vein bypasses the liver completely. E-PRUV has a worse prognosis compared to I-PRUV, due either to severe hemodynamic effects or to the frequent association with other severe fetal malformations. CASE: Here we report a case of E-PRUV with good outcome. Prenatal fetal ultrasonography (US) performed at 33 weeks of gestation in 28-year old woman, highlights the presence of E-PRUV with right UV draining in inferior vena cava. In the male neonate born at 35 weeks of gestation by C-section, the Apgar Score was 95`- 1010 and no other associated malformations and hemodynamic decompensation were found. Postnatal abdominal US showed the presence of enlarged paraumbilical veins. CONCLUSIONS: The association of E-PRUV draining into the inferior vena cava with shunt through paraumbilical veins, could have preserved offspring by severe cardiac overload, positively affecting prognosis.
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Feto , Ultrasonografía Prenatal , Adulto , Femenino , Humanos , Masculino , Vena Porta , Embarazo , Pronóstico , Venas Umbilicales/diagnóstico por imagenRESUMEN
Guidelines advice against dual antiplatelet therapy (DAPT) discontinuation less than 12 months after percutaneous coronary intervention with drug-eluting stents (DES-PCI). However, any delay of necessary surgery in patients with descending thoracic (DTA) or abdominal aortic aneurysm (AAA), treated by DES-PCI, increases the risk of aneurysm rupture/dissection. We evaluated the safety of 8-week waiting time between DES-PCI and endovascular aortic repair (EVAR). 1152 consecutive patients with coronary artery disease (CAD) needing elective DTA or AAA repair were enrolled and divided into two groups. Group A included 830 patients treated by DES-PCI for significant CAD who underwent surgery 8 weeks after implantation. Group B included 322 patients treated by DES-PCI at least 6 months before with no residual significant CAD and treated by elective EVAR. Groups were compared according to a composite of death, myocardial infarction, stent thrombosis, cerebrovascular events and bleeding. No aneurysm rupture/dissection occurred while waiting for surgery. Hospital averse events occurred in 6.2% (52/830) group A patients versus 6.5% (21/322) group B patients (p = 0.8). Mortality was 0.7% (6/830) in group A and 0.9% (3/322) in group B (p = 0.7). Multivariate predictors of events were triple vessel DES-PCI (p < 0.001), > 3 stents implanted (p < 0.001), early-generation stents (p < 0.001), diabetes insulin requiring (p = 0.01), stent diameter < 3.0 mm (p = 0.009) and total stented length > 30 mm (p = 0.02). Eight weeks of waiting after DES-PCI in addition to an adequate management of DAPT were safe in terms of cardiac morbidity and bleeding complications. No aneurysm rupture occurred in the interval before surgery.
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Aneurisma de la Aorta/cirugía , Enfermedad de la Arteria Coronaria/cirugía , Procedimientos Quirúrgicos Electivos/métodos , Procedimientos Endovasculares/métodos , Intervención Coronaria Percutánea/métodos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Espera Vigilante/métodos , Anciano , Anciano de 80 o más Años , Aneurisma Roto/prevención & control , Aneurisma de la Aorta/complicaciones , Estudios de Cohortes , Enfermedad de la Arteria Coronaria/complicaciones , Stents Liberadores de Fármacos , Femenino , Hemorragia/epidemiología , Hemorragia/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Seguridad , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND AND AIM OF THE STUDY: The outcome of mitral valve (MV) repair for chronic ischemic mitral regurgitation (IMR) is suboptimal, due to the high recurrence rate of moderate or severe mitral regurgitation (MR) during follow-up. The MV adapts to new MR increasing its area to cover the enlarged annular area (mitral plasticity). As this process is often incomplete, we aimed to evaluate if augmenting the anterior leaflet (AL) and cutting the second-order chords (CC) together with restrictive mitral annuloplasty, a strategy we call "surgical mitral plasticity," could improve the midterm results of MV repair for IMR. MATERIALS AND METHODS: From November 2017 to October 2019, 22 patients with chronic IMR underwent surgical mitral plasticity. Mean age was 73 ± 7 years and six were female. Mean ejection fraction was 32% ± 11%, IMR grade was moderate in 10 and severe in 12. Mean clinical and echocardiographic follow-up was 12 ± 6 months. RESULTS: There was no early death, and one patient died 6 months after surgery. Ejection fraction improved from 32% ± 15% to 40% ± 6% (P = .031). IMR was absent or mild in all patients, and none showed recurrent moderate or more IMR. Tenting area decreased significantly from 2.5 ± 0.5 to 0.5 ± 0.3 cm² and coaptation length increased from 1.9 ± 0.7 to 7.8 ± 1.6 mm. All patients were in New York Heart Association class I or II. CONCLUSIONS: Mitral plasticity, if uncomplete, is ineffective in preventing IMR to become significant. Surgical mitral plasticity, by completing incomplete process of MV adaptation, has a strong rationale, which however needs to be validated with longer follow-up.
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Anuloplastia de la Válvula Mitral/métodos , Insuficiencia de la Válvula Mitral/cirugía , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Resultado del TratamientoRESUMEN
Late aneurysm formation in the proximal aorta or distal aortic arch is a recognized sequela of untreated stenosis of the aortic isthmus and is associated with substantial risk of aortic rupture. We describe the case of a 44-year-old man with untreated coarctation of the aorta who presented with a prestenotic dissecting thoracic aortic aneurysm. He declined surgery because he was a Jehovah's Witness. Instead, we performed emergency endovascular aortic repair in which 2 stent-grafts were placed in the descending aorta. Our experience suggests that this procedure is a useful and safe alternative to open surgery in patients who have aneurysms associated with coarctation of the aorta.
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Aorta Torácica/cirugía , Aneurisma de la Aorta Torácica/cirugía , Coartación Aórtica/complicaciones , Disección Aórtica/cirugía , Prótesis Vascular , Procedimientos Endovasculares/métodos , Testigos de Jehová , Adulto , Disección Aórtica/diagnóstico , Disección Aórtica/etiología , Angiografía , Aorta Torácica/diagnóstico por imagen , Aneurisma de la Aorta Torácica/diagnóstico , Aneurisma de la Aorta Torácica/etiología , Coartación Aórtica/diagnóstico , Coartación Aórtica/cirugía , Humanos , Imagenología Tridimensional , Masculino , Diseño de Prótesis , Tomografía Computarizada por Rayos XRESUMEN
AIMS: Mortality and left ventricular mass (LVM) recovery/regression after aortic valve replacement in patients with prosthesis-patient mismatch (PPM) is controversial. This study evaluated the impact of different values of indexed effective orifice area (EOAi) in male patients on mortality and indexed LVM (ILVM) recovery/regression. METHOD: The study recruited 376 male patients with and without PPM after aortic valve replacement with different EOAi cut-off values. RESULTS: At EOAi 0.85âcm/m or less, 295 patients had PPM (78.5%). ILVM recovery occurred in 60.5% of no-PPM patients versus 46.1% of patients with PPM (Pâ=â0.003), and ILVM regression was 35 versus 25% (Pâ<â0.001). Time for ILVM regression was shorter in no-PPM group. At EOAi 0.75âcm/m or less, 201 patients had PPM (53.4%). ILVM recovery occurred in 55.4% of no-PPM patients versus 45.2% of patients with PPM (Pâ=â0.06), regression was 32 versus 29% (Pâ=â0.09). Time for ILVM regression was similar between groups. Regardless the cut-off value for PPM definition, mortality was similar. CONCLUSION: LVM recovery/regression, but not mortality, was different at different EOAi. The cut-off value at EOAi 0.75âcm/m or less guaranteed a more balanced patient distribution between groups and the best compromise between specificity and sensitivity.