ABSTRACT
AIMS: The aim of this study is to evaluate the effect of beta-blockers and angiotensin receptor blockers in reducing the aortic growth rate in children with bicuspid aortic valve (BAV)-related aortopathy and ascending phenotype. METHODS: Consecutive paediatric patients (≤16 years) with BAV and ascending aorta (AsAo) dilation (z-score > 3) were enrolled in this observational retrospective cohort study. Patients receiving prophylactic treatment with either atenolol (0.5 to 1.0 mg/kg/daily) or losartan (0.7 to 1.4 mg/kg/daily) were compared with those who did not receive medical prophylaxis (control group). The primary outcome of interest was the annual rate of change in maximal AsAo diameter z-score in the treatment and control groups. RESULTS: From a cohort of 1005 patients, 120 (mean age 11.3 ± 4.5 years, 82% males) fulfilled the inclusion criteria and were included in the study. Patients in the treatment and control group had similar age, sex, family history of BAV, BAV morphology, and baseline AsAo diameter. During a median follow-up of 7.1 years (interquartile range 3.8-10.2), no differences were observed in the annual growth rate of aortic diameter z-score between patients on treatment and controls. The prevalence of aortic diameter progression was similar in the treatment and control groups, and treatment with atenolol or losartan was not associated with a lower rate of aortic disease progression. CONCLUSIONS: The findings revealed no significant difference in the annual aortic growth rate between treated and untreated patients. Larger cohort studies or, ideally, randomized clinical controlled trials are needed to validate these findings.
Subject(s)
Adrenergic beta-Antagonists , Aortic Valve , Bicuspid Aortic Valve Disease , Humans , Male , Female , Child , Retrospective Studies , Adolescent , Adrenergic beta-Antagonists/therapeutic use , Aortic Valve/abnormalities , Aortic Valve/diagnostic imaging , Aortic Valve/pathology , Aortic Valve/drug effects , Angiotensin Receptor Antagonists/therapeutic use , Losartan/therapeutic use , Follow-Up Studies , Cohort Studies , Atenolol/therapeutic use , Treatment Outcome , Aorta/drug effects , Aorta/diagnostic imaging , Aortic Valve Disease/drug therapy , Heart Valve Diseases/drug therapy , Heart Valve Diseases/complications , Angiotensin II Type 1 Receptor Blockers/therapeutic useABSTRACT
BACKGROUND: Ascending aorta dilation and aortic valve degeneration are common complications in patients with bicuspid aortic valve. Several retrospective studies have suggested the benefit of statins in reducing these complications. This study aimed to determine whether atorvastatin treatment is effective in reducing the growth of aortic diameters in bicuspid aortic valve and if it slows the progression of valve calcification. METHODS: In a randomized clinical trial, 220 patients with bicuspid aortic valve (43 women; 46±13 years of age) were included and treated with either 20 mg of atorvastatin per day or placebo for 3 years. Inclusion criteria were ≥18 years of age, nonsevere valvular dysfunction, nonsevere valve calcification, and ascending aorta diameter ≤50 mm. Computed tomography and echocardiography studies were performed at baseline and after 3 years of treatment. RESULTS: During follow-up, 28 patients (12.7%) discontinued medical treatment (15 on atorvastatin and 13 taking placebo). Thus, 192 patients completed the 36 months of treatment. Low-density lipoprotein cholesterol levels decreased significantly in the atorvastatin group (median [interquartile range], -30 mg/dL [-51.65 to -1.75 mg/dL] versus 6 mg/dL [-4, 22.5 mg/dL]; P<0.001). The maximum ascending aorta diameter increased with no differences between groups: 0.65 mm (95% CI, 0.45-0.85) in the atorvastatin group and 0.74 mm (95% CI, 0.45-1.04) in the placebo group (P=0.613). Similarly, no significant differences were found for the progression of the aortic valve calcium score (P=0.167) or valvular dysfunction. CONCLUSIONS: Among patients with bicuspid aortic valve without severe valvular dysfunction, atorvastatin treatment was not effective in reducing the progression of ascending aorta dilation and aortic valve calcification during 3 years of treatment despite a significant reduction in low-density lipoprotein cholesterol levels. REGISTRATION: URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2015-001808-57. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02679261.
Subject(s)
Aortic Valve , Atorvastatin , Bicuspid Aortic Valve Disease , Calcinosis , Disease Progression , Heart Valve Diseases , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Atorvastatin/therapeutic use , Female , Male , Middle Aged , Aortic Valve/diagnostic imaging , Aortic Valve/pathology , Aortic Valve/abnormalities , Aortic Valve/drug effects , Calcinosis/drug therapy , Calcinosis/diagnostic imaging , Calcinosis/pathology , Bicuspid Aortic Valve Disease/diagnostic imaging , Bicuspid Aortic Valve Disease/drug therapy , Heart Valve Diseases/drug therapy , Heart Valve Diseases/diagnostic imaging , Heart Valve Diseases/pathology , Adult , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Dilatation, Pathologic/drug therapy , Follow-Up Studies , Double-Blind Method , Treatment Outcome , Aorta/diagnostic imaging , Aorta/pathology , Aorta/drug effects , Aortic Valve Disease/drug therapy , Aortic Valve StenosisABSTRACT
Mapping the gene-regulatory networks dysregulated in human disease would allow the design of network-correcting therapies that treat the core disease mechanism. However, small molecules are traditionally screened for their effects on one to several outputs at most, biasing discovery and limiting the likelihood of true disease-modifying drug candidates. Here, we developed a machine-learning approach to identify small molecules that broadly correct gene networks dysregulated in a human induced pluripotent stem cell (iPSC) disease model of a common form of heart disease involving the aortic valve (AV). Gene network correction by the most efficacious therapeutic candidate, XCT790, generalized to patient-derived primary AV cells and was sufficient to prevent and treat AV disease in vivo in a mouse model. This strategy, made feasible by human iPSC technology, network analysis, and machine learning, may represent an effective path for drug discovery.
Subject(s)
Aortic Valve Disease/drug therapy , Aortic Valve Stenosis/drug therapy , Aortic Valve/pathology , Calcinosis/drug therapy , Gene Regulatory Networks/drug effects , Machine Learning , Nitriles/pharmacology , Nitriles/therapeutic use , Thiazoles/pharmacology , Thiazoles/therapeutic use , Algorithms , Animals , Aortic Valve/drug effects , Aortic Valve/metabolism , Aortic Valve/physiopathology , Aortic Valve Disease/genetics , Aortic Valve Disease/physiopathology , Aortic Valve Stenosis/genetics , Aortic Valve Stenosis/physiopathology , Calcinosis/genetics , Calcinosis/physiopathology , Disease Models, Animal , Drug Discovery , Drug Evaluation, Preclinical , Gene Expression Regulation/drug effects , Haploinsufficiency , Humans , Induced Pluripotent Stem Cells , Mice, Inbred C57BL , RNA-Seq , Receptor, Notch1/genetics , Small Molecule LibrariesABSTRACT
Corynebacterium kroppenstedtii is an emerging cause of granulomatous mastitis and recurrent breast abscesses in women, but data on its clinical relevance in nongynecological disease conditions are limited. Here, we report the first case of a late-onset endocarditis of a native aortic valve in a 73-year-old male patient who presented with symptomatic aortic insufficiency. Echocardiography and cardiac computed tomography revealed the perforation of the noncoronary cusp and a large perivalvular abscess cavity. Hence, the surgical replacement of the aortic valve and aortic root were performed. Intraoperatively obtained tissue specimens grew C. kroppenstedtii and the patient made a full recovery after a 6-week course of antibiotic treatment. We briefly review the literature pertaining to antimicrobial susceptibility patterns of C. kroppenstedtii and available treatment recommendations. Our report calls for further studies to assess the role of this bacterium as a causative agent of infections other than granulomatous mastitis.
Subject(s)
Aortic Valve Disease/microbiology , Corynebacterium Infections/complications , Corynebacterium , Aged , Anti-Bacterial Agents/therapeutic use , Aortic Valve Disease/diagnosis , Aortic Valve Disease/drug therapy , Corynebacterium Infections/diagnosis , Corynebacterium Infections/microbiology , Endocarditis, Bacterial/drug therapy , Endocarditis, Bacterial/microbiology , Humans , MaleABSTRACT
CONTEXTO: La insuficiencia mitral (IM) se caracteriza por el reflujo anormal de sangre desde el ventrículo Izquierdo a la aurícula izquierda durante la sístole, causado por alteraciones estructurales primarias del aparato valvular (valvas, anillos y músculos papilares) o funcionales en presencia de disfunción ventricular. Su pronóstico depende de la gravedad de la disfunción ventricular izquierda. En Estadios Unidos la prevalencia en la población general del 1,7%, donde las formas moderadas a severas afectan a uno de cada diez individuos mayores de 75 años de edad, siendo la prevalencia em este grupo etario cercana a un 13 %. El tratamiento quirúrgico, mediante reemplazo o reparación quirúrgica, es el tratamiento de elección en la IM estructural sintomática severa. Cerca de un 50% de estos pacientes son rechazados para la estrategia quirúrgica por ser considerados grupo de riesgo alto definido por el deterioro de la función sistólica ventricular izquierda (FSVI), edad avanzada y comorbilidades clínicas. El tratamiento médico en la IM puede reducir los síntomas en algunos casos, pero no puede modificar la historia natural de la enfermedad. De esta manera, los individuos no intervenidos experimentan progresión de la insuficiencia cardíaca congestiva (ICC) con una consecuente mala calidad de vida y muerte. Es en este contexto que surgen estrategias terapéuticas menos invasivas, como la reparación mitral percutánea con el sistema MitraClip®. Se postula el uso de dispositivos tipos MitraClip® para pacientes con insuficiencia cardiaca moderada o severa que presenten valvulopatía mitral. TECNOLOGÍA: El dispositivo MitraClip® está diseñado para la reparación percutánea de la válvula mitral insuficiente, a la cual se accede mediante cateterización venosa femoral y punción auricular transeptal com anestesia general bajo guía fluoroscópica y ecocardiográfica transesofágica. El sistema se compone de un catéter guía y grapas de acero inoxidable que mediante la aproximación y clipeado tisular de las valvas anterior y posterior mitrales busca reducir el reflujo transvalvular. Es un procedimiento de muy alta complejidad que debe realizarse en establecimientos que posean equipo de hemodinámica de alta calidad, ecocardiograma transesofágico con capacidad de realizar imágenes 3D, equipo de cirugía cardiovascular de respaldo, anestesia general y una unidad de cuidado intensivo coronario. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de dispositivo MitraClip® en la insuficiência mitral modera o severa. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas, en buscadores genéricos de internet, y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS), evaluaciones económicas, guías de práctica clínica (GPC) y políticas de cobertura de diferentessistemas de salud. RESULTADOS: Se incluyeron tres ECAs, una RS, seis GPC, tres ETS, una evaluación económica, y catorce informes de políticas de cobertura para uso de dispositivo MitraClip® en la insuficiencia mitral moderada o severa. CONCLUSIONES: Evidencia de moderada calidad es contradictoria con respecto a la efectividad del uso del dispositivo MitraClip® para reducir la mortalidad en pacientes con insuficiencia mitral sintomática com tratamiento médico estándar a dosis máximas, riesgo quirúrgico elevado o contraindicación quirúrgica. Un estudio demostró MitraClip® mejoraría la mortalidad cardiovascular y las tasas de re-hospitalización por insuficiencia cardíaca en pacientes con insuficiencia mitral moderada o severa al año y a los dos años, mientras que otro no encontró diferencias al año en pacientes con insuficiência mitral severa y mayor deterioro de la función ventricular con comorbilidades graves asociadas. Evidencia alta calidad muestra que el uso del dispositivo MitraClip® en pacientes con insuficiência mitral moderada o severa sintomática, con criterios de cirugía y sin contraindicación a la misma; no reduce las tasas de mortalidad o mejora los síntomas de insuficiencia cardiaca asociada al año cuando se la compara con la cirugía valvular. La mortalidad a los 5 años fue similar entre ambos tratamientos. En el grupo de pacientes tratado con el dispositivo, las tasas de re-operación dentro del año fueron mayores. Las guías de práctica clínica y los financiadores de salud latinoamericanos, europeos y estadounidenses definen que la primera línea de tratamiento para reemplazo o reparación de la válvula mitral es la cirugía. La reparación percutánea con dispositivos tipo MitraClip® estaría indicada en pacientes con insuficiencia mitral severa que presenten sintomatología grave clase funcional III-IV de la NYHA, con dosis máximas de tratamiento médico, con una esperanza de vida razonable y un riesgo quirúrgico elevado debido a comorbilidades severas. Estudios de costo-efectividad europeos sugieren que el uso de este dispositivo podría ser costo-efectivo dado la disminución de costos asociados a hospitalizaciones de pacientes con insuficiência cardiaca por valvulopatía mitral cuando se compara versus tratamiento médico y/o quirúrgico.
Subject(s)
Humans , Sutures/supply & distribution , Equipment and Supplies/supply & distribution , Catheters/supply & distribution , Aortic Valve Disease/drug therapy , Mitral Valve/physiopathology , Health EvaluationABSTRACT
Calcific aortic valve disease (CAVD) is highly prevalent with marked morbidity and mortality rates and a lack of pharmaceutical treatment options because its mechanisms are unknown. Melatonin is reported to exert atheroprotective effects. However, whether melatonin protects against aortic valve calcification, a disease whose pathogenesis shares many similarities to that of atherosclerosis, and the underlying molecular mechanisms remain unknown. In this study, we found that the intragastric administration of melatonin for 24 weeks markedly ameliorated aortic valve calcification in high cholesterol diet (HCD)-treated ApoE-/- mice, as evidenced by reduced thickness and calcium deposition in the aortic valve leaflets, improved echocardiographic parameters (decreased transvalvular peak jet velocity and increased aortic valve area), and decreased osteogenic differentiation marker (Runx2, osteocalcin, and osterix) expression in the aortic valves. Consistent with these in vivo data, we also confirmed the suppression of in vitro calcification by melatonin in hVICs. Mechanistically, melatonin reduced the level of CircRIC3, a procalcification circular RNA, which functions by acting as a miR-204-5p sponge to positively regulate the expression of the procalcification gene dipeptidyl peptidase-4 (DPP4). Furthermore, CircRIC3 overexpression abolished the inhibitory effects of melatonin on hVIC osteogenic differentiation. Taken together, our results suggest that melatonin ameliorates aortic valve calcification via the regulation of CircRIC3/miR-204-5p/DPP4 signaling in hVICs; therefore, melatonin medication might be considered a novel pharmaceutical strategy for CAVD treatment.
