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BACKGROUND: Patients with repaired Tetralogy of Fallot (rTOF) experience a high burden of long-term morbidity, particularly arrhythmias. Cardiovascular magnetic resonance (CMR) is routinely used to assess ventricular characteristics but the relationship between CMR diastolic function and arrhythmia has not been evaluated. We hypothesized in rTOF, left ventricular (LV) diastolic dysfunction on CMR would correlate with arrhythmias and mortality. METHODS: Adolescents and adults with rTOF who underwent CMR were compared to healthy controls (n = 58). Standard ventricular parameters were assessed and manual planimetry was performed to generate filling curves and indices of diastolic function. Chart review was performed to collect outcomes. Univariate and multivariable logistic regression was performed to identify outcome associations. RESULTS: One-hundred sixty-seven subjects with rTOF (mean age 32 years) and 58 healthy control subjects underwent CMR. Patients with rTOF had decreased LV volumes and increased right ventricular (RV) volumes, lower RV ejection fraction (RVEF), lower peak ejection rate (PER), peak filling rate (PFR) and PFR indexed to end-diastolic volume (PFR/EDV) compared to healthy controls. Eighty-three subjects with rTOF had arrhythmia (63 atrial, 47 ventricular) and 11 died. Left atrial (LA) volumes, time to peak filling rate (tPFR), and PFR/EDV were associated with arrhythmia on univariate analysis. PER/EDV was associated with ventricular (Odds ratio, OR 0.43 [0.24-0.80], p = 0.007) and total arrhythmia (OR 0.56 [0.37-0.92], p = 0.021) burden. A multivariable predictive model including diastolic covariates showed improved prediction for arrhythmia compared to clinical and conventional CMR measures (area under curve (AUC) 0.749 v. 0.685 for overall arrhythmia). PFR/EDV was decreased and tPFR was increased in rTOF subjects with mortality as compared to those without mortality. CONCLUSIONS: Subjects with rTOF have abnormal LV diastolic function compared to healthy controls. Indices of LV diastolic function were associated with arrhythmia and mortality. CMR diastolic indices may be helpful in risk stratification for arrhythmia.
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Fibrilación Atrial , Tetralogía de Fallot , Disfunción Ventricular Izquierda , Disfunción Ventricular Derecha , Adulto , Adolescente , Humanos , Valor Predictivo de las Pruebas , Atrios Cardíacos , Función Ventricular Derecha , Espectroscopía de Resonancia Magnética , Estudios RetrospectivosRESUMEN
BACKGROUND: Diastolic dysfunction is associated with morbidity and mortality in multiple pediatric disease processes. Cardiovascular magnetic resonance (CMR) provides a non-invasive method of studying left ventricular (LV) diastolic dysfunction through the assessment of LV filling curves and left atrial (LA) volume and function. However, there are no normative data for LV filling curves and the standard method is time-intensive. This study aims to compare an alternate, more rapid method of obtaining LV filling curves to standard methodology and report normative CMR diastolic function data for LV filling curves and LA volumes and function. METHODS: Ninety-six healthy pediatric subjects (14.3 ± 3.4 years) with normal CMR defined by normal biventricular size and systolic function without late gadolinium enhancement were included. LV filling curves were generated by removing basal slices without myocardium present throughout the cardiac cycle and apical slices with poor endocardial delineation (compressed method), then re-generated including every phase of myocardium from apex to base (standard method). Indices of diastolic function included peak filling rate and time to peak filling. Systolic metrics included peak ejection rate and time to peak ejection. Both peak ejection and peak filling rates were indexed to end-diastolic volume. LA maximum, minimum and pre-contraction volumes were calculated using a biplane method. Inter-and intra-observer variability were assessed with intraclass correlation coefficient. Multivariable linear regression was used to assess the effects of body surface area (BSA), gender and age on metrics of diastolic function. RESULTS: BSA had the largest effect on LV filling curves. Normal LV filling data are reported for both compressed and standard methods. The time to perform the compressed method was significantly shorter than the standard method (median 6.1 min vs. 12.5 min, p < 0.001). Both methods had strong to moderate correlation for all metrics. Intra-observer reproducibility was moderate to high for all LV filling and LA metrics except for time to peak ejection and peak filling. CONCLUSIONS: We report reference values for LV filling metrics and LA volumes. The compressed method is more rapid and produces similar results to standard methodology, which may facilitate the use of LV filling in clinical CMR reporting.
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Medios de Contraste , Gadolinio , Niño , Humanos , Reproducibilidad de los Resultados , Valor Predictivo de las Pruebas , Ventrículos Cardíacos , Función Atrial , Atrios Cardíacos , Espectroscopía de Resonancia MagnéticaRESUMEN
BACKGROUND: Cardiac magnetic resonance (CMR) strain can be assessed with feature-tracking (FT), which utilizes a post-processing algorithm to quantify myocardial deformation on routine cine images, and strain-encoding magnetic resonance imaging (SENC), which uses parallel magnetization tags combined with out-of-plane phase-encoding gradients to quantify deformation. Assessing agreement is critical to determine whether results can be translated between methods. We compared SENC to FT in the assessment of left ventricle (LV) global longitudinal strain (GLS) and global circumferential strain (GCS) in a cohort of pediatric and adult congenital heart disease (ACHD) patients. METHODS: Pediatric subjects and ACHD patients underwent CMR on 1.5 T Siemens scanners, including balanced steady-state-free precession (bSSFP) cine imaging and SENC acquisitions in apical two and four chamber, left ventricular outflow tract, and short axis views. bSSFP cine imaging FT analysis was completed with Medis QStrain. Myocardial Solutions MyoStrain was used to analyze SENC. Correlation was assessed by Spearman's rank correlation coefficient. Agreement between techniques was assessed with concordance correlation coefficient (CCC) and Bland-Altman. RESULTS: The cohort included 134 patients, 75 with congenital heart disease (56%). The median age was 16.3 years (IQR 13.7, 19.5). Median LV ejection fraction was 57% (IQR 54.4, 61.6). SENC and FT were in poor agreement for GLS (Spearman's ρ = 0.58, p < 0.001; CCC 0.24) and GCS (Spearman's ρ = 0.29, p < 0.001; CCC 0.03). CONCLUSION: There was poor agreement between SENC and FT derived GLS and GCS in a cohort of pediatric and ACHD patients, suggesting that SENC and FT cannot be used interchangeably.
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Cardiopatías Congénitas , Función Ventricular Izquierda , Adolescente , Adulto , Niño , Cardiopatías Congénitas/diagnóstico por imagen , Humanos , Imagen por Resonancia Cinemagnética/métodos , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Volumen SistólicoRESUMEN
BACKGROUND: Contrast enhanced magnetic resonance imaging (MRI) is an important tool for the assessment of extracardiac vasculature and myocardial viability. Gadolinium (Gd) brain deposition after contrast enhanced MRI has recently been described and resulted in a warning issued by the United States Food and Drug Administration. However, the prevalence of brain deposition in children and adults with congenital heart disease (CHD) undergoing cardiovascular magnetic resonance (CMR) is unclear. We hypothesized that Gd exposure as part of one or more CMRs would lead to a low rate of brain deposition in pediatric and adult CHD patients. METHODS: We queried our institutional electronic health record for all pediatric and adult CHD patients who underwent contrast enhanced CMR from 2005 to 2018 and had a subsequent brain MRI. Cases were age- and gender-matched to controls who were never exposed to Gd and underwent brain MRIs. The total number of contrast enhanced MRIs, type of Gd, and total Gd dose were determined. Brain MRIs were reviewed by a neuroradiologist for evidence of Gd deposition using qualitative and quantitative assessment. Quantitative assessment was performed using the dentate nucleus to pons signal intensity ratio (dp-SIR) on T1 weighted imaging. Continuous variables were analyzed using Mann-Whitney U and Spearman rank correlation tests. Normal SIR was defined as the 95% CI of the control population dp-SIR. RESULTS: Sixty-two cases and 62 controls were identified. The most contrast enhanced MRIs in a single patient was five and the largest lifetime dose of Gd that any patient received was 0.75 mmol/kg. There was no significant difference in the mean dp-SIR of cases and controls (p = 0.11). The dp-SIR was not correlated with either the lifetime dose of Gd (rs = 0.21, p = 0.11) or the lifetime number of contrast enhanced studies (rs = 0.21, p = 0.11). Two cases and 2 controls had dp-SIRs above the upper bound of the 95% confidence interval for the control group. One case had qualitative imaging-based evidence of Gd deposition in the brain but had a dp-SIR within the normal range. CONCLUSION: In our cohort of pediatric and adult CHD patients undergoing contrast enhanced CMR, there was a low incidence of qualitative and no significant quantitative imaging-based evidence of Gd brain deposition.
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Encéfalo/metabolismo , Medios de Contraste/metabolismo , Gadolinio/metabolismo , Cardiopatías Congénitas/diagnóstico por imagen , Imagen por Resonancia Magnética , Adolescente , Adulto , Niño , Preescolar , Medios de Contraste/administración & dosificación , Registros Electrónicos de Salud , Femenino , Gadolinio/administración & dosificación , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Distribución Tisular , Adulto JovenRESUMEN
BACKGROUND: Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Standard cardiac biomarkers are poor indicators of DMD cardiovascular disease. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) regulate collagen turnover. Given the cardiac fibrosis seen in DMD, we hypothesized that MMPs and TIMPs correlate with severity of DMD cardiomyopathy. METHODS AND RESULTS: Prospectively enrolled DMD subjects (nâ¯=â¯42) underwent cardiac magnetic resonance imaging for function and late gadolinium enhancement (LGE), including LGE severity from 0 (no LGE) to 4 (severe). Serum from DMD and healthy male control subjects (nâ¯=â¯15) analyzed for MMPs 1, 2, 3, 7, 9, and 10 and TIMPs 1-4. MMP1, MMP7, and MMP10 were higher in DMD than in control (respectively, median 5080 pg/mL vs 2120 pg/mL [Pâ¯=â¯.007], 2170 pg/mL vs 1420 pg/mL [P < .001], and 216 pg/mL vs 140pg/mL [Pâ¯=â¯.040]); TIMP4 was lower in DMD (124 pg/mL vs 263 pg/mL; Pâ¯=â¯.046). Within DMD, MMP7 correlated inversely with left ventricular ejection fraction (râ¯=â¯-0.40; Pâ¯=â¯.012) and directly with strain (râ¯=â¯0.54; Pâ¯=â¯.001) and LGE severity (râ¯=â¯0.47; Pâ¯=â¯.003). MMP7 was higher in DMD patients with LGE compared with those without LGE and control subjects (P < .001). CONCLUSIONS: Multiple MMPs are elevated in DMD compared with control subjects. MMP7 is related to DMD cardiac dysfunction and myocardial fibrosis, possibly through remodeling of the extracellular matrix.
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Cardiomiopatías/metabolismo , Metaloproteinasas de la Matriz/sangre , Distrofia Muscular de Duchenne/metabolismo , Inhibidores Tisulares de Metaloproteinasas/sangre , Adolescente , Adulto , Biomarcadores/metabolismo , Biopsia , Cardiomiopatías/diagnóstico , Cardiomiopatías/etiología , Niño , Colágeno/metabolismo , Femenino , Fibrosis/diagnóstico , Fibrosis/etiología , Fibrosis/metabolismo , Estudios de Seguimiento , Humanos , Imagen por Resonancia Cinemagnética/métodos , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distrofia Muscular de Duchenne/complicaciones , Distrofia Muscular de Duchenne/diagnóstico , Miocardio/patología , Estudios Prospectivos , Adulto JovenRESUMEN
INTRODUCTION: Distinguishing between hypertrophic cardiomyopathy and other causes ofleft ventricular hypertrophy can be difficult in children. We hypothesised that cardiac MRI T1 mapping could improve diagnosis of paediatric hypertrophic cardiomyopathy and that measures of myocardial function would correlate with T1 times and extracellular volume fraction. METHODS: Thirty patients with hypertrophic cardiomyopathy completed MRI with tissue tagging, T1-mapping, and late gadolinium enhancement. Left ventricular circumferential strain was calculated from tagged images. T1, partition coefficient, and synthetic extracellular volume were measured at base, mid, apex, and thickest area of myocardial hypertrophy. MRI measures compared to cohort of 19 healthy children and young adults. Mann-Whitney U, Spearman's rho, and multivariable logistic regression were used for statistical analysis. RESULTS: Hypertrophic cardiomyopathy patients had increased left ventricular ejection fraction and indexed mass. Hypertrophic cardiomyopathy patients had decreased global strain and increased native T1 (-14.3% interquartile range [-16.0, -12.1] versus -17.3% [-19.0, -15.7], p < 0.001 and 1015 ms [991, 1026] versus 990 ms [972, 1001], p = 0.019). Partition coefficient and synthetic extracellular volume were not increased in hypertrophic cardiomyopathy. Global native T1 correlated inversely with ejection fraction (ρ = -0.63, p = 0.002) and directly with global strain (ρ = 0.51, p = 0.019). A logistic regression model using ejection fraction and native T1 distinguished between hypertrophic cardiomyopathy and control with an area under the receiver operating characteristic curve of 0.91. CONCLUSION: In this cohort of paediatric hypertrophic cardiomyopathy, strain was decreased and native T1 was increased compared with controls. Native T1 correlated with both ejection fraction and strain, and a model using native T1 and ejection fraction differentiated patients with and without hypertrophic cardiomyopathy.
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Cardiomiopatía Hipertrófica/diagnóstico por imagen , Imagen por Resonancia Cinemagnética , Miocardio/patología , Función Ventricular Izquierda , Adolescente , Adulto , Fenómenos Biomecánicos , Cardiomiopatía Hipertrófica/fisiopatología , Estudios de Casos y Controles , Niño , Medios de Contraste/administración & dosificación , Femenino , Gadolinio/administración & dosificación , Humanos , Modelos Logísticos , Masculino , Valor Predictivo de las Pruebas , Curva ROC , Volumen Sistólico , Remodelación Ventricular , Adulto JovenRESUMEN
There is controversy regarding the management of projectile embolization, a rare complication of penetrating trauma. We present the case of a 5-year-old, 20 kg male with retrograde venous projectile embolization following traumatic injury with a pellet gun. The projectile was successfully removed utilizing a novel, percutaneous approach.
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Embolia/cirugía , Cuerpos Extraños/cirugía , Lesiones Cardíacas/cirugía , Heridas por Arma de Fuego/complicaciones , Preescolar , Embolia/etiología , Cuerpos Extraños/complicaciones , Lesiones Cardíacas/complicaciones , Lesiones Cardíacas/etiología , Humanos , Masculino , Heridas por Arma de Fuego/cirugíaRESUMEN
Turner syndrome (TS) patients with hypoplastic left heart syndrome (HLHS) have poor single ventricle palliation outcomes; therefore, consideration of other potential management strategies is important. Little is known about heart transplantation (HTx) in this group, as standard HTx databases do not allow for identification of TS. This study describes experiences and outcomes of HTx in TS using a unique linkage between the Scientific Registry of Transplant Recipients and the Pediatric Health Information System databases. All pediatric HTx recipients (2002-2016) with TS were identified in the database using ICD-9 code 758.6 (gonadal dysgenesis) in conjunction with female sex. Patient characteristics and outcomes were described. Fourteen patients with TS were identified who underwent 16 HTx procedures at eight centers. For initial HTx, HLHS was the most common indication (10/14) with a median age of 10 months (IQR 3-73 months). Median transplant-free survival following initial HTx was 4.1 years (IQR 16 days-10.5 years), with all deaths occurring in the first year post-HTx. For patients that survived past 1 year (8/14), follow-up ranged from 4.1 to 10.9 years (median 8.0 years) with no deaths observed. Our cohort demonstrates that while there is a clear risk for early mortality, there is the potential for favorable outcomes following HTx in patients with TS. Therefore, TS should not be viewed as an absolute contraindication to HTx, but careful assessment of candidate risk is needed. Primary palliation with HTx for HLHS and TS may be a reasonable consideration given the poor outcomes of single ventricle palliation in this group. Further research is needed to fully delineate the outcomes and characteristics of this unique population.
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Trasplante de Corazón/tendencias , Síndrome del Corazón Izquierdo Hipoplásico/cirugía , Síndrome de Turner/complicaciones , Adolescente , Niño , Preescolar , Bases de Datos Factuales , Femenino , Estudios de Seguimiento , Trasplante de Corazón/mortalidad , Humanos , Síndrome del Corazón Izquierdo Hipoplásico/complicaciones , Lactante , Recién Nacido , Cuidados Paliativos , Sistema de Registros , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Mutación de Línea Germinal , Hipertensión Pulmonar/genética , Animales , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Caveolina 1/genética , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
BACKGROUND: Congenitally corrected transposition of the great arteries (ccTGA) has many management strategies, with the emergence of anatomic repair increasing the available surgical options. Contemporary surgical practices have not been described in multicenter analyses. This study describes the distribution of heart surgery in patients with ccTGA and defines contemporary outcomes in a large multicenter cohort. METHODS: Index cardiovascular operations in patients with primary or fundamental diagnosis of ccTGA were identified in The Society of Thoracic Surgeons Congenital Heart Surgery Database from 2010 to 2019. Operations of interest were combined into mutually exclusive groups designating overall ccTGA management strategies. Outcomes were defined with standard Society of Thoracic Surgeons Congenital Heart Surgery Database definitions. Pearson χ2 and Kruskal-Wallis tests were used for statistical comparisons. RESULTS: One hundred one centers performed 985 index operations, with anatomic repair the most common approach. Twenty-six centers performed more than 10 operations. Atrial switch plus Rastelli operations had the highest rate of operative mortality (8.4%) and major complications (38.2%). Heart transplant operations had the longest postoperative length of stay among survivors (18 days [interquartile range, 13.5-26]). CONCLUSIONS: Patients with ccTGA remain a challenging cohort, with significant diversity in the operations used and a substantial burden of operative mortality and morbidity.
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Operación de Switch Arterial , Procedimientos Quirúrgicos Cardíacos , Cirujanos , Transposición de los Grandes Vasos , Humanos , Transposición Congénitamente Corregida de las Grandes Arterias , Transposición de los Grandes Vasos/complicaciones , Resultado del TratamientoRESUMEN
BACKGROUND: Turner syndrome (TS) is a genetic syndrome characterized by monosomy X (45,XO) in phenotypic females and is commonly associated with congenital heart disease. We sought to describe the distribution, mortality, and morbidity of congenital heart surgery in TS and compare outcomes to individuals without genetic syndromes. METHODS: The Society of Thoracic Surgeons Congenital Heart Surgery Database was used to evaluate index cardiovascular operations performed from 2000 to 2017 in pediatric patients (aged 0-18 years) with and without TS. Analyses were stratified by the most common operations, including coarctation repair, aortic arch repair, partial anomalous pulmonary venous return repair, Norwood, superior cavopulmonary anastomosis (Glenn), and Fontan. RESULTS: Included were 780 operations in TS and 62,659 operations in controls. The most common TS operations were coarctation repair in 274 (35%), aortic arch repair in 116 (15%), and Norwood in 59 (8%). Compared with controls, TS patients had lower weight-for-age Z-scores across all operations (P < .01 for all); however, operative mortality rates did not differ significantly. The chylothorax rate was higher in TS after coarctation repair (8.8% vs 2.8%, P < .001) and Norwood (22% vs 8.1%, P < .001). The median (interquartile range) postoperative length of stay was longer in TS for coarctation repair (6.5 [5.0-15.5] days vs 5.0 [4.0-9.0] days, P < .001), aortic arch repair (15.0 [8.0-27.5] days vs 11.0 [7.0-21.0] days, P = .004), and Glenn (9.0 [6.0-16.0] days vs 6.0 [5.0-11.0] days, P = .013). CONCLUSIONS: Turner syndrome patients most commonly underwent operations for left-sided obstructive lesions. Despite increased morbidity for select operations, TS was not associated with increased operative mortality.
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Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/cirugía , Síndrome de Turner/complicaciones , Adolescente , Procedimientos Quirúrgicos Cardíacos/métodos , Niño , Preescolar , Estudios de Cohortes , Bases de Datos Factuales , Femenino , Humanos , Lactante , Complicaciones Posoperatorias/epidemiología , Sociedades Médicas , Cirugía Torácica , Resultado del TratamientoRESUMEN
Biomarkers are routinely used for noninvasive identification or monitoring of disease processes in clinical practice, as well as surrogate end points for drug development. There is a significant lack of data regarding biomarkers in children. An understanding of biomarker levels in a healthy pediatric cohort is essential as more studies begin to apply noninvasive biomarkers to pediatric populations. Brain-derived neurotrophic factor (BDNF) functions in neuronal survival and plasticity and is associated with exercise capacity and inflammatory disease processes. Osteopontin (OPN) plays a regulatory role in inflammation and may be a clinically useful biomarker of cardiovascular disease processes, ventricular remodeling, and skeletal muscle regeneration. This study describes our initial experience with a cohort of healthy pediatric patients and seeks to provide normal values of BDNF and OPN with correlation to age, gender, and cardiovascular and fitness measures. Serum BDNF and plasma OPN were measured using enzyme-linked immunosorbent assay in 33 healthy pediatric subjects. Subjects underwent complete cardiac evaluation, including echocardiography, exercise stress testing, and health risk assessment. The 5th-95th percentile was 5.63-37.86 ng/ml for serum BDNF and 4.9-164.9 ng/ml for plasma OPN. Plasma OPN correlated with number of days of exercise per week (r = 0.46, p = 0.008). No other correlations were significant. This study provides the initial data on serum BDNF and plasma OPN in children and begins to explore the relationships of BDNF and OPN to cardiovascular health and fitness in the pediatric population.
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We report the case of a 9-month-old male with Williams syndrome who underwent patch augmentation of supravalvar aortic stenosis and pulmonary artery stenosis, and required emergent drug-eluting left coronary artery stenting on post-operative day 1 for severe left ventricular dysfunction related to myocardial ischemia.
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BACKGROUND: Both statins and ezetimibe lower LDL-C, but ezetimibe's effect on atherosclerosis is controversial. We hypothesized that lowering LDL-C cholesterol by adding ezetimibe to statin therapy would regress atherosclerosis measured by magnetic resonance imaging (MRI) in the superficial femoral artery (SFA) in peripheral arterial disease (PAD). METHODS: Atherosclerotic plaque volume was measured in the proximal 15-20 cm of the SFA in 67 PAD patients (age 63 ± 10, ABI 0.69 ± 0.14) at baseline and annually × 2. Statin-naïve patients (n=34) were randomized to simvastatin 40 mg (S, n=16) or simvastatin 40 mg+ezetimibe 10mg (S+E, n=18). Patients already on statins but with LDL-C >80 mg/dl had open-label ezetimibe 10mg added (E, n=33). Repeated measures models estimated changes in plaque parameters over time and between-group differences. RESULTS: LDL-C was lower at year 1 in S+E (67 ± 7 mg/dl) than S (91 ± 8 mg/dl, p<0.05), but similar at year 2 (68 ± 10 mg/dl vs. 83 ± 11 mg/dl, respectively). Plaque volume did not change from baseline to year 2 in either S+E (11.5 ± 1.4-10.5 ± 1.3 cm(3), p=NS) or S (11.0 ± 1.5-10.5 ± 1.4 cm(3), p=NS). In E, plaque progressed from baseline to year 2 (10.0 ± 0.8-10.8 ± 0.9, p<0.01) despite a 22% decrease in LDL-C. CONCLUSIONS: Statin initiation with or without ezetimibe in statin-naïve patients halts progression of peripheral atherosclerosis. When ezetimibe is added to patients previously on statins, peripheral atherosclerosis progressed. Thus, ezetimibe's effect on peripheral atherosclerosis may depend upon relative timing of statin therapy.
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Aterosclerosis/tratamiento farmacológico , Azetidinas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Enfermedad Arterial Periférica/tratamiento farmacológico , Anciano , Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/sangre , Método Doble Ciego , Ezetimiba , Femenino , Arteria Femoral/efectos de los fármacos , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/tratamiento farmacológico , Estudios Prospectivos , Simvastatina/administración & dosificación , Resultado del TratamientoRESUMEN
Prostaglandin (PG) E(2), a major product of activated macrophages, has been implicated in atherosclerosis and plaque rupture. The PGE(2) receptors, EP2 and EP4, are expressed in atherosclerotic lesions and are known to inhibit apoptosis in cancer cells. To examine the roles of macrophage EP4 and EP2 in apoptosis and early atherosclerosis, fetal liver cell transplantation was used to generate LDLR(-/-) mice chimeric for EP2(-/-) or EP4(-/-) hematopoietic cells. After 8 weeks on a Western diet, EP4(-/-) --> LDLR(-/-) mice, but not EP2(-/-) --> LDLR(-/-) mice, had significantly reduced aortic atherosclerosis with increased apoptotic cells in the lesions. EP4(-/-) peritoneal macrophages had increased sensitivity to proapoptotic stimuli, including palmitic acid and free cholesterol loading, which was accompanied by suppression of activity of p-Akt, p-Bad, and NF-kappaB-regulated genes. Thus, EP4 deficiency inhibits the PI3K/Akt and NF-kappaB pathways compromising macrophage survival and suppressing early atherosclerosis, identifying macrophage EP4-signaling pathways as molecular targets for modulating the development of atherosclerosis.