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BACKGROUND: HIV and hepatitis C virus (HCV) are associated with increased risk of carotid artery atherosclerotic plaque and stroke. We examined associations of HIV- and HCV-related factors with echomorphologic features of carotid artery plaque. METHODS: This cross-sectional study included participants from the MACS (Multicenter AIDS Cohort Study)/WIHS (Women's Interagency HIV Study) Combined Cohort Study who underwent high-resolution B-mode carotid artery ultrasound. Plaques were characterized from 6 areas of the right carotid artery. Poisson regression controlling for demographic and cardiometabolic risk factors determined adjusted prevalence ratios (aPRs) and 95% CIs for associations of HIV- and HCV-related factors with echomorphologic features. RESULTS: Of 2655 participants (65% women, median age 44 [interquartile range, 37-50] years), 1845 (70%) were living with HIV, 600 (23%) were living with HCV, and 425 (16%) had carotid plaque. There were 191 plaques identified in 129 (11%) women with HIV, 51 plaques in 32 (7%) women without HIV, 248 plaques in 171 (28%) men with HIV, and 139 plaques in 93 (29%) men without HIV. Adjusted analyses showed that people with HIV and current CD4+ count <200 cells/µL had a significantly higher prevalence of predominantly echolucent plaque (aPR, 1.86 [95% CI, 1.08-3.21]) than those without HIV. HCV infection alone (aPR, 1.86 [95% CI, 1.08-3.19]) and HIV-HCV coinfection (aPR, 1.75 [95% CI, 1.10-2.78]) were each associated with higher prevalence of predominantly echogenic plaque. HIV-HCV coinfection was also associated with higher prevalence of smooth surface plaque (aPR, 2.75 [95% CI, 1.03-7.32]) compared with people without HIV and HCV. CONCLUSIONS: HIV with poor immunologic control, as well as HCV infection, either alone or in the presence of HIV, were associated with different echomorphologic phenotypes of carotid artery plaque.
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Enfermedades de las Arterias Carótidas , Estenosis Carotídea , Coinfección , Infecciones por VIH , Hepatitis C , Placa Aterosclerótica , Adulto , Femenino , Humanos , Masculino , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/epidemiología , Enfermedades de las Arterias Carótidas/complicaciones , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/epidemiología , Estenosis Carotídea/complicaciones , Estudios de Cohortes , Coinfección/diagnóstico por imagen , Coinfección/epidemiología , Coinfección/complicaciones , Estudios Transversales , Hepacivirus , Hepatitis C/complicaciones , Hepatitis C/diagnóstico por imagen , Hepatitis C/epidemiología , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnóstico por imagen , Infecciones por VIH/epidemiología , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/epidemiología , Placa Aterosclerótica/complicaciones , Factores de Riesgo , Persona de Mediana Edad , Estudios Multicéntricos como AsuntoRESUMEN
Over the last two decades, implantable continuous flow left ventricular assist devices (LVAD) have proven to be invaluable tools for the management of selected advanced heart failure patients, improving patient longevity and quality of life. The presence of concomitant valvular pathology, including that involving the tricuspid, mitral, and aortic valve, has important implications relating to the decision to move forward with LVAD implantation. Furthermore, the presence of concomitant valvular pathology often influences the surgical strategy for LVAD implantation. Concomitant valve repair or replacement is not uncommonly required in such circumstances, which increases surgical complexity and has demonstrated prognostic implications both short and longer term following LVAD implantation. Beyond the index operation, it is also well established that certain valvular pathologies may develop or worsen over time following LVAD support. The presence of pre-existing valvular pathology or that which develops following LVAD implant is of particular importance to the destination therapy LVAD patient population. As these patients are not expected to have the opportunity for heart transplantation in the future, optimization of LVAD support including ameliorating valvular disease is critical for the maximization of patient longevity and quality of life. As collective experience has grown over time, the ability of clinicians to effectively address concomitant valvular pathology in LVAD patients has improved in the pre-implant, implant, and post-implant phase, through both medical management and procedural optimization. Nevertheless, there remains uncertainty over many facets of concomitant valvular pathology in advanced heart failure patients, and the understanding of how to best approach these conditions in the LVAD patient population continues to evolve. Herein, we present a comprehensive review of the current state of the field relating to the pathophysiology and management of valvular disease in destination LVAD patients.
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Left ventricular assist device (LVAD) therapy is a lifesaving option for patients with medical therapy-refractory advanced heart failure. Depending on the definition, 5-44% of people supported with an LVAD develop right heart failure (RHF), which is associated with worse outcomes. The mechanisms related to RHF include patient, surgical, and hemodynamic factors. Despite significant progress in understanding the roles of these factors and improvements in surgical techniques and LVAD technology, this complication is still a substantial cause of morbidity and mortality among LVAD patients. Additionally, specific medical therapies for this complication still are lacking, leaving cardiac transplantation or supportive management as the only options for LVAD patients who develop RHF. While significant effort has been made to create algorithms aimed at stratifying risk for RHF in patients undergoing LVAD implantation, the predictive value of these algorithms has been limited, especially when attempts at external validation have been undertaken. Perhaps one of the reasons for poor performance in external validation is related to differing definitions of RHF in external cohorts. Additionally, most research in this field has focused on RHF occurring in the early phase (i.e., ≤1 month) post LVAD implantation. However, there is emerging recognition of late-onset RHF (i.e., > 1 month post-surgery) as a significant cause of morbidity and mortality. Late-onset RHF, which likely has a unique physiology and pathogenic mechanisms, remains poorly characterized. In this review of the literature, we will describe the unique right ventricular physiology and changes elicited by LVADs that might cause both early- and late-onset RHF. Finally, we will analyze the currently available treatments for RHF, including mechanical circulatory support options and medical therapies.
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The utilization of left ventricular assist devices (LVADs) in end-stage heart failure has doubled in the past ten years and is bound to continue to increase. Since the first of these devices was approved in 1994, the technology has changed tremendously, and so has the medical and surgical management of these patients. In this review, we discuss the history of LVADs, evaluating survival and complications over time. We also aim to discuss practical aspects of the medical and surgical management of LVAD patients and future directions for outcome improvement in this population.
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BACKGROUND: Heart failure predisposes to intracardiac thrombus (ICT) formation. There are limited data on the prevalence and impact of preexisting ICT on postoperative outcomes in left ventricular assist device patients. We examined the risk for stroke and death in this patient population. METHODS AND RESULTS: We retrospectively studied patients who were implanted with HeartMate (HM) II or HM3 between February 2009 and March 2019. Preoperative transthoracic echocardiograms, intraoperative transesophageal echocardiograms and operative reports were reviewed to identify ICT. There were 525 patients with a left ventricular assist device (median age 60.6 years, 81.8% male, 372 HMII and 151 HM3) included in this analysis. An ICT was identified in 44 patients (8.4%). During the follow-up, 43 patients experienced a stroke and 55 died. After multivariable adjustment, presence of ICT increased the risk for the composite of stroke or death at 6-month (hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.00-3.33, Pâ¯=â¯.049). Patients with ICT were also at higher risk for stroke (HR 2.45, 95% CI 1.14-5.28, Pâ¯=â¯.021) and death (HR 2.36, 95% CI 1.17-4.79 Pâ¯=â¯.016) at 6 months of follow-up. CONCLUSIONS: The presence of ICT is an independent predictor of stroke and death at 6 months after left ventricular assist device implantation. Additional studies are needed to help risk stratify and optimize the perioperative management of this patient population.
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Insuficiencia Cardíaca , Corazón Auxiliar , Accidente Cerebrovascular , Trombosis , Femenino , Insuficiencia Cardíaca/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Trombosis/diagnóstico por imagen , Trombosis/epidemiología , Resultado del TratamientoRESUMEN
INTRODUCTION: Outcomes in acute decompensated heart failure (ADHF) have remained poor. Worsening renal function (WRF) is common among patients with ADHF. However, the impact of WRF on the prognosis is controversial. We hypothesized that in patients with ADHF, the achievement of concomitant decongestion would diminish the signal for harm associated with WRF. METHODS: We performed a systematic search of PubMed, EMBASE, and the Cochrane Library up to December 2019 for studies that assessed signs of decongestion in patients with WRF during ADHF admission. The primary outcome was all-cause mortality and heart transplantation. RESULTS: Thirteen studies were selected with a pooled population of 8138 patients. During the follow-up period of 60-450 days, 19.2% of patients died. Unstratified, patients with WRF versus no WRF had a higher risk for mortality (odds ratio [OR], 1.71 [95% confidence interval {CI}, 1.45-2.01]; P < 0.0001). However, patients who achieved decongestion had a similar prognosis (OR, 1.15 [95% CI, 0.89-1.49]; P = 0.30). Moreover, patients with WRF who achieved decongestion had a better prognosis compared with those without WRF or decongestion (OR, 0.63 [95% CI, 0.46-0.86]; P = 0.004). This tendency persisted for the sensitivity analyses. CONCLUSIONS: Decongestion is a powerful effect modifier that attenuates harmful associations of WRF with mortality. Future studies should not assess WRF as an endpoint without concomitant assessment of achieved volume status.
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Background People living with HIV have an increased risk of left ventricular diastolic dysfunction (LVDD) and heart failure. HIV-associated LVDD may reflect both cardiomyocyte and systemic metabolic derangements, but the underlying pathways remain unclear. Methods and Results To explore such pathways, we conducted a pilot study in the Bronx and Brooklyn sites of the WIHS (Women's Interagency HIV Study) who participated in concurrent, but separate, metabolomics and echocardiographic ancillary studies. Liquid chromatography tandem mass spectrometry-based metabolomic profiling was performed on plasma samples from 125 HIV-infected (43 with LVDD) and 35 HIV-uninfected women (9 with LVDD). Partial least squares discriminant analysis identified polar metabolites and lipids in the glycerophospholipid-metabolism and fatty-acid-oxidation pathways associated with LVDD. After multivariable adjustment, LVDD was significantly associated with higher concentrations of diacylglycerol 30:0 (odds ratio [OR], 1.60, 95% CI [1.01-2.55]); triacylglycerols 46:0 (OR 1.60 [1.04-2.48]), 48:0 (OR 1.63 [1.04-2.54]), 48:1 (OR 1.62 [1.01-2.60]), and 50:0 (OR 1.61 [1.02-2.53]); acylcarnitine C7 (OR 1.88 [1.21-2.92]), C9 (OR 1.99 [1.27-3.13]), and C16 (OR 1.80 [1.13-2.87]); as well as lower concentrations of phosphocholine (OR 0.59 [0.38-0.91]). There was no evidence of effect modification of these relationships by HIV status. Conclusions In this pilot study, women with or at risk of HIV with LVDD showed alterations in plasma metabolites in the glycerophospholipid-metabolism and fatty-acid-oxidation pathways. Although these findings require replication, they suggest that improved understanding of metabolic perturbations and their potential modification could offer new approaches to prevent cardiac dysfunction in this high-risk group.
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Metabolismo Energético , Infecciones por VIH/sangre , Metabolómica , Disfunción Ventricular Izquierda/sangre , Función Ventricular Izquierda , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/fisiopatología , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Persona de Mediana Edad , Proyectos Piloto , Pronóstico , Medición de Riesgo , Factores Sexuales , Estados Unidos/epidemiología , Disfunción Ventricular Izquierda/epidemiología , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
BACKGROUND: Bivalirudin may be an effective alternative anticoagulant to heparin for use in percutaneous peripheral interventions. We aimed to compare the safety and efficacy of bivalirudin versus heparin as the procedural anticoagulant agent in patients undergoing percutaneous peripheral intervention. METHODS: For this meta-analysis and systematic review, we conducted a search in PubMed, Medline, Embase, and Cochrane for all the clinical studies in which bivalirudin was compared to heparin as the procedural anticoagulant in percutaneous peripheral interventions. Outcomes studied included all-cause mortality, all-bleeding, major and minor bleeding, and access site complications. RESULTS: Eleven studies were included in the analysis, totaling 20,137 patients. There was a significant difference favoring bivalirudin over heparin for all-cause mortality (risk ratio 0.58, 95% CI 0.39-0.87), all-bleeding (risk ratio 0.62, 95% CI 0.50-0.78), major bleeding (risk ratio 0.61, 95% CI 0.39-0.96), minor bleeding (risk ratio 0.66, 95% CI 0.47-0.92), and access site complications (risk ratio 0.66, 95% CI 0.51-0.84). There was no significant difference in peri-procedural need for blood transfusions (risk ratio 0.79, 95% CI 0.57-1.08), myocardial infarction (risk ratio 0.87, 95% CI 0.59-1.28), stroke (risk ratio 0.77, 95% CI 0.59-1.01), intracranial bleeding (risk ratio 0.77, 95% CI 0.29-2.02), or amputations (OR 0.75, 95% CI 0.53-1.05). CONCLUSION: Our meta-analysis suggests that bivalirudin use for percutaneous peripheral interventions is associated with lower all-cause mortality, bleeding, and access site complications as compared to heparin. Further large randomized trials are needed to confirm the current results.
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Anticoagulantes/administración & dosificación , Antitrombinas/administración & dosificación , Cateterismo Periférico , Procedimientos Endovasculares , Heparina/administración & dosificación , Hirudinas/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Enfermedad Arterial Periférica/terapia , Trombosis/prevención & control , Anciano , Anticoagulantes/efectos adversos , Antitrombinas/efectos adversos , Cateterismo Periférico/efectos adversos , Cateterismo Periférico/mortalidad , Procedimientos Endovasculares/efectos adversos , Procedimientos Endovasculares/mortalidad , Femenino , Hemorragia/inducido químicamente , Heparina/efectos adversos , Hirudinas/efectos adversos , Humanos , Masculino , Fragmentos de Péptidos/efectos adversos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Medición de Riesgo , Factores de Riesgo , Trombosis/etiología , Trombosis/mortalidad , Resultado del TratamientoRESUMEN
The intra-aortic balloon pump (IABP) and percutaneous ventricular assist devices (pVAD) are commonly used in different clinical scenarios. The goal of this study was to carry out a meta-analysis and Trial Sequential Analysis (TSA) comparing the IABP versus pVAD (TandemHeart and the Impella) during high-risk percutaneous coronary intervention (PCI) or cardiogenic shock (CS). Using PubMed, Cochrane Central Register of Controlled Trials, and EMBASE we searched for randomized clinical trials (RCTs) and nonrandomized studies that compared pVAD versus IABP in patients who underwent high-risk PCI or with CS. We included 5 RCTs and 1 nonrandomized study comparing pVAD versus IABP. Based on the RCTs, we demonstrated no difference in short-term (6 months) (risk ratio [RR] 1.09, 95% confidence interval [CI] 0.79 to 1.52; pâ¯=â¯0.59) or long-term (12 months) (RR 1.00, 95% CI 0.57 to 1.76; pâ¯=â¯1.00) all-cause mortality. The use of pVAD seemed associated with more adverse events (acute kidney injury, limb ischemia, infection, major bleeding, and vascular injury) compared with IABP (RR 1.65, 95% CI 1.14 to 2.39; pâ¯=â¯0.008) but this was not supported by TSA (random-effects RR 1.66, 95% CI 0.89 to 3.09; pâ¯=â¯0.11; TSA-adjusted CI 0.13 to 21.3). In conclusion there were no differences in short or long-term mortality when using IABP versus pVAD for high-risk PCI or CS. IABP showed superiority over pVAD in terms of risk of harm. However, further RCTs are needed to establish more conclusively the role of these modalities of mechanical circulatory support during high-risk PCI or CS.
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Corazón Auxiliar , Contrapulsador Intraaórtico , Intervención Coronaria Percutánea , Choque Cardiogénico/complicaciones , Choque Cardiogénico/terapia , Humanos , Seguridad del Paciente , Factores de RiesgoRESUMEN
We developed a novel adenylyl cyclase type 5 (AC5) inhibitor, C90, that reduces myocardial infarct size even when administered after coronary reperfusion. This is key, since it is not practical to administer a drug to a patient with myocardial infarction before revascularization, and is one reason why so many prior drugs, which reduced infarct in experimental animals, failed in clinical trials. C90 is the most potent AC5 inhibitor, as exhibited by its IC50 value for AC5 inhibition, which was 5 times lower than the next most potent AC5 inhibitor. C90 reduced cAMP in response to forskolin in wild type mice by 42%, but no longer reduced cAMP in response to forskolin in mice with disruption of AC5, indicating that the mechanism of C90 was specific for AC5 inhibition. Compared with vehicle treatment, C90 reduced infarct size by 64% at a dose of 0.6â¯mg/kg. Thus, C90 is a novel, selective and potent AC5 inhibitor that reduces infarct size, when delivered after coronary artery reperfusion, rendering it potentially clinically useful. It also reduces beta-adrenergic receptor signaling, which will provide additional benefit to patients with coronary artery disease or heart failure.
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Adenilil Ciclasas/genética , Inhibidores Enzimáticos/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Infarto del Miocardio/tratamiento farmacológico , Adenilil Ciclasas/efectos de los fármacos , Animales , Colforsina/toxicidad , AMP Cíclico/genética , AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Humanos , Ratones , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/enzimología , Infarto del Miocardio/patología , Reperfusión Miocárdica/métodos , Receptores Adrenérgicos beta/genética , Transducción de Señal/efectos de los fármacosRESUMEN
BACKGROUND: Multi-vessel coronary disease in people with ST elevation myocardial infarction (STEMI) is common and is associated with worse prognosis after STEMI. Based on limited evidence, international guidelines recommend intervention on only the culprit vessel during STEMI. This, in turn, leaves other significantly stenosed coronary arteries for medical therapy or revascularisation based on inducible ischaemia on provocative testing. Newer data suggest that intervention on both the culprit and non-culprit stenotic coronary arteries (complete intervention) may yield better results compared with culprit-only intervention. OBJECTIVES: To assess the effects of early complete revascularisation compared with culprit vessel only intervention strategy in people with STEMI and multi-vessel coronary disease. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, World Health Organization International Clinical Trials Registry Platform Search Portal, and ClinicalTrials.gov. The date of the last search was 4 January 2017. We applied no language restrictions. We handsearched conference proceedings to December 2016, and contacted authors and companies related to the field. SELECTION CRITERIA: We included only randomised controlled trials (RCTs), wherein complete revascularisation strategy was compared with a culprit-only percutaneous coronary intervention (PCI) for the treatment of people with STEMI and multi-vessel coronary disease. DATA COLLECTION AND ANALYSIS: We assessed the methodological quality of each trial using the Cochrane 'Risk of bias' tool. We resolved the disagreements by discussion among review authors. We followed standard methodological approaches recommended by Cochrane. The primary outcomes were long-term (one year or greater after the index intervention) all-cause mortality, long-term cardiovascular mortality, long-term non-fatal myocardial infarction, and adverse events. The secondary outcomes were short-term (within the first 30 days after the index intervention) all-cause mortality, short-term cardiovascular mortality, short-term non-fatal myocardial infarction, revascularisation, health-related quality of life, and cost. We analysed data using fixed-effect models, and expressed results as risk ratios (RR) with 95% confidence intervals (CI). We used GRADE criteria to assess the quality of evidence and we conducted Trial Sequential Analysis (TSA) to control risks of random errors. MAIN RESULTS: We included nine RCTs, that involved 2633 people with STEMI and multi-vessel coronary disease randomly assigned to either a complete (n = 1381) versus culprit-only (n = 1252) revascularisation strategy. The complete and the culprit-only revascularisation strategies did not differ for long-term all-cause mortality (65/1274 (5.1%) in complete group versus 72/1143 (6.3%) in culprit-only group; RR 0.80, 95% CI 0.58 to 1.11; participants = 2417; studies = 8; I2 = 0%; very low quality evidence). Compared with culprit-only intervention, the complete revascularisation strategy was associated with a lower proportion of long-term cardiovascular mortality (28/1143 (2.4%) in complete group versus 51/1086 (4.7%) in culprit-only group; RR 0.50, 95% CI 0.32 to 0.79; participants = 2229; studies = 6; I2 = 0%; very low quality evidence) and long-term non-fatal myocardial infarction (47/1095 (4.3%) in complete group versus 70/1004 (7.0%) in culprit-only group; RR 0.62, 95% CI 0.44 to 0.89; participants = 2099; studies = 6; I2 = 0%; very low quality evidence). The complete and the culprit-only revascularisation strategies did not differ in combined adverse events (51/2096 (2.4%) in complete group versus 57/1990 (2.9%) in culprit-only group; RR 0.84, 95% CI 0.58 to 1.21; participants = 4086; I2 = 0%; very low quality evidence). Complete revascularisation was associated with lower proportion of long-term revascularisation (145/1374 (10.6%) in complete group versus 258/1242 (20.8%) in culprit-only group; RR 0.47, 95% CI 0.39 to 0.57; participants = 2616; studies = 9; I2 = 31%; very low quality evidence). TSA of long-term all-cause mortality, long-term cardiovascular mortality, and long-term non-fatal myocardial infarction showed that more RCTs are needed to reach more conclusive results on these outcomes. Regarding long-term repeat revascularisation more RCTs may not change our present result. The quality of the evidence was judged to be very low for all primary and the majority of the secondary outcomes mainly due to risk of bias, imprecision, and indirectness. AUTHORS' CONCLUSIONS: Compared with culprit-only intervention, the complete revascularisation strategy may be superior due to lower proportions of long-term cardiovascular mortality, long-term revascularisation, and long-term non-fatal myocardial infarction, but these findings are based on evidence of very low quality. TSA also supports the need for more RCTs in order to draw stronger conclusions regarding the effects of complete revascularisation on long-term all-cause mortality, long-term cardiovascular mortality, and long-term non-fatal myocardial infarction.
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Estenosis Coronaria/cirugía , Revascularización Miocárdica/métodos , Infarto del Miocardio con Elevación del ST/cirugía , Causas de Muerte , Estenosis Coronaria/complicaciones , Estenosis Coronaria/mortalidad , Femenino , Humanos , Masculino , Revascularización Miocárdica/efectos adversos , Revascularización Miocárdica/mortalidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Infarto del Miocardio con Elevación del ST/etiología , Infarto del Miocardio con Elevación del ST/mortalidadRESUMEN
A 24-year-old female who was recently diagnosed with Type 1 diabetes mellitus (TiD) presented with a five-year history of visible gait disturbance and slurred speech. Her neurologic examination was remarkable for dysarthria, bilateral nystagmus, dysdiadochokinesia, finger-nose incoordination, heel-knee incoordination, and ataxic gait. A brain MRI disclosed diffuse cerebellar atrophy. Her serum antiglutamic acid decarboxylase (GAD) antibody titer was elevated. Antinuclear antibody (ANA) test was positive with atiterofl:2560 and a speckledpattern. Genetictests for inherited ataxia, including Friedreich ataxia, were negative for mutations. Her cerebrospinal fluid (CSF) analysis revealed oligoclonal bands and she had a positive CSF GAD65 antibody. A diag- nosis of GAD antibody-induced cerebellar ataxia was considered. She developed GAD autoimmune antibody positive TiD during the course ofher dis- ease. GAD antibody-associated cerebellar ataxia is a rare entity, however it should be considered as a possibility in patients with associated autoimmune disease and positive anti-GAD antibody.
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Anticuerpos/sangre , Ataxia Cerebelosa/sangre , Ataxia Cerebelosa/complicaciones , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/complicaciones , Glutamato Descarboxilasa/inmunología , Femenino , Humanos , Adulto JovenRESUMEN
A Food and Drug Administration-approved antiviral agent, known as vidarabine or adenine 9-ß-D-arabinofuranoside (AraA), has features of inhibiting adenylyl cyclase type 5 (AC5) and protects against chronic coronary artery occlusion (CAO). The goal of this investigation was to determine whether AraA protects against myocardial ischemia, even when delivered after coronary artery reperfusion (CAR). AraA, delivered after CAR in wild-type mice, reduced infarct size by 55% compared with vehicle-treated controls, whereas an equal dose of adenosine reduced infarct size only when administered before CAR. A 5-fold greater dose of adenosine was required to reduce infarct size when delivered after CAR, which also reduced arterial pressure by 15%, whereas AraA did not affect pressure. The reduction in infarct size with AraA was prevented by a MEK/extracellular signal-regulated kinase blocker, a pathway also involved in the mechanism of protection of the AC5 knockout (KO) model. Infarct size was also reduced in cardiac-specific AC5 KO mice similarly in the presence and absence of AraA, further suggesting that AraA protection involves the AC5 pathway. AraA reduced infarct size in chronically instrumented conscious pigs when delivered after CAR, and in this model, it also reduced post-CAR coronary hyperemia, which could be another mechanism for cardioprotection (i.e., by reducing oxidative stress during CAR). Thus, AraA inhibits AC5 and exhibits unique cardioprotection when delivered after CAR, which is critical for clinical translation.