Treatment of pediatric heterozygous familial hypercholesterolemia 7 years after the EAS recommendations: Real-world results from a large French cohort.

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) predisposes to premature cardiovascular diseases. Since 2015, the European Atherosclerosis Society has advocated initiation of statins at 8-10 years of age and a low-density lipoprotein cholesterol (LDL-C) target of <135 mg/dL. Longitudinal data from large databases on pharmacological management of pediatric HeFH are lacking. OBJECTIVE: Here, we describe treatment patterns and LDL-C goal attainment in pediatric HeFH using longitudinal real-world data. METHODS: This was a retrospective and prospective multicenter cohort study (2015-2021) of children with HeFH, diagnosed genetically or clinically, aged <18 years, and followed up in the National French Registry of FH (REFERCHOL). Data on the study population as well as treatment patterns and outcomes are summarized as mean±SD. RESULTS: We analyzed the data of 674 HeFH children (age at last visit: 13.1 ± 3.6 years; 82.0 % ≥10 years; 52.5 % females) who were followed up for a mean of 2.8 ± 3.5 years. Initiation of lipid-lowering therapy was on average at 11.8 ± 3.0 years of age for a duration of 2.5 ± 2.8 years. At the last visit, among patients eligible for treatment (573), 36 % were not treated, 57.1 % received statins alone, 6.4 % statins with ezetimibe, and 0.2 % ezetimibe alone. LDL-C was 266±51 mg/dL before treatment and 147±54 mg/dL at the last visit (-44.7 %) in treated patients. Regarding statins, 3.3 %, 65.1 %, and 31.6 % of patients received high-, moderate-, and low-intensity statins, respectively. Overall, 59 % of children on statin therapy alone and 35.1 % on bitherapy did not achieve the LDL-C goal; fewer patients in the older age group did not reach the treatment goal. CONCLUSION: Pediatric patients with FH followed up in specialist lipid clinics in France receive late treatment, undertreatment, or suboptimal treatment and half of them do not reach the therapeutic LDL-C goal. Finding a more efficient framework for linking scientific evidence to clinical practice is needed.

Cholesterol trafficking, lysosomal function, and atherosclerosis.

Despite years of study and major research advances over the past 50 years, atherosclerotic diseases continue to rank as the leading global cause of death. Accumulation of cholesterol within the vascular wall remains the main problem and represents one of the early steps in the development of atherosclerotic lesions. There is a complex relationship between vesicular cholesterol transport and atherosclerosis, and abnormalities in cholesterol trafficking can contribute to the development and progression of the lesions. The dysregulation of vesicular cholesterol transport and lysosomal function fosters the buildup of cholesterol within various intracytoplasmic compartments, including lysosomes and lipid droplets. This, in turn, promotes the hallmark formation of foam cells, a defining feature of early atherosclerosis. Multiple cellular processes, encompassing endocytosis, exocytosis, intracellular trafficking, and autophagy, play crucial roles in influencing foam cell formation and atherosclerotic plaque stability. In this review, we highlight recent advances in the understanding of the intricate mechanisms of vesicular cholesterol transport and its relationship with atherosclerosis and discuss the importance of understanding these mechanisms in developing strategies to prevent or treat this prevalent cardiovascular disease.

Impact of Preoperative Protein Sparing Modified Fast Diet on Bariatric Surgery.

INTRODUCTION: Bariatric surgery can become technically challenging in the setting of liver steatosis and hepatomegaly. The protein sparing modified fast (PSMF) diet helps in achieving rapid weight loss. The aim of this study is to explore the results of a preoperative PSMF diet on liver volume and steatosis as well as on intraoperative and postoperative complications in patients with hepatomegaly undergoing Roux-en-Y gastric bypass (RYGB). METHODS: Between January 2010 and January 2021, 713 patients undergoing RYGB as a primary bariatric surgery were divided in two groups. Those with a measured liver length above 16 cm and or evidence of liver steatosis on ultrasound (group 1) were offered a preoperative PSMF diet while the remaining (group 2) proceeded directly to surgery. Between January 2010 and April 2012, patients included in group 1 had liver volume measurements on magnetic resonance imaging the day before the diet was started and the day before the surgery. For the length of the study, intraoperative and postoperative data were recorded for both groups. RESULTS: Five days of preoperative PSMF diet resulted in a significant reduction of total and left liver volume (15.8% and 21% respectively, p < 0.001). There was no difference in intraoperative bleeding and conversion rate or postoperative complication rate between both groups. CONCLUSION: The PSMF diet helps in achieving a rapid decrease in liver volume. Patients with hepatomegaly initially thought to be at a higher risk of intraoperative complications reached comparable rates to patients without hepatomegaly after the diet regimen without any impact on the postoperative course.

Factors Predicting Statin Initiation During Childhood in Familial Hypercholesterolemia: Importance of Genetic Diagnosis.

OBJECTIVE: To identify childhood and parental factors associated with initiation of statin therapy in children with heterozygous familial hypercholesterolemia (HeFH), including underlying genetic diagnosis or parental premature atherosclerotic cardiovascular disease (ASCVD). STUDY DESIGN: This multicenter cohort study included 245 HeFH child-parent pairs from the REFERCHOL national register (2014-2020). Demographic and clinical characteristics at the last visit were collected. Vascular disease in parents was defined as a history of ASCVD, and/or a coronary artery calcium score >100, and/or stenosis of >50% in at least carotid artery. Statistical analyses included descriptive analysis, logistic regression for univariate and multivariate effects of statins, and a sensitivity analysis combining the characteristics of children and parents. RESULTS: Among the 245 children in the study cohort, 135 (58%), with a mean age of 14 ± 3 years, were treated with a statin. In multivariable analysis, the predictive childhood factors associated with statin treatment were genetic diagnosis (OR, 2.5; 95% CI, 1.3 to 4.9; P = .01), older age (OR, 4.4; 95% CI, 1.8-10.6; P = .01), more than 2 visits (OR, 2.36; 95% CI, 1.18-4.73; P = .015), and longer duration of follow-up (OR, 1.3; 95% CI, 1.1-1.6; P < .001). The predictive parental factor associated with childhood treatment was the presence of vascular disease (OR, 2.4; 95% CI, 1.0-5.7; P = .04). CONCLUSIONS: HeFH confirmed by DNA testing during childhood and a history of vascular disease in parents were independently associated with statin treatment in children with HeFH. Genetic diagnosis may be useful for cardiovascular prevention in children.

Spontaneous Intracranial Hypotension: An Etiology for Consciousness Disorder and Coma.

We report 3 cases of spontaneous intracranial hypotension (SIH) associated with consciousness disorder and coma. In patients, SIH was suspected on a computed tomography scan and diagnosed by cerebral magnetic resonance imaging (MRI). Spinal MRI confirmed cerebrospinal fluid leakage. SIH should be seen as an underestimated cause of consciousness disorder and coma, especially in patients with a history of orthostatic headache, spinal injury, or oculomotor signs. Computed tomography scans should be examined for signs of SIH before operating on patients with a spontaneous subdural hematoma. Brain and spine MRI should be performed when SIH is suspected. Our 3 patients have shown good recovery without any neurological sequelae.

Detection of silent myocardial ischemia in asymptomatic patients with diabetes: results of a randomized trial and meta-analysis assessing the effectiveness of systematic screening.

BACKGROUND: Most guidelines recommend a systematic screening of asymptomatic high risk patients with diabetes for silent ischemia, but the clinical benefit of this strategy has not been demonstrated compared with the simple control of cardiovascular risk factors. We sought to determine whether referring asymptomatic diabetic patients for screening of silent ischemia decreases the risk of cardiovascular events compared with usual care. METHODS: DYNAMIT was a prospective, randomized, open, blinded end-point multicenter trial run between 2000 and 2005, with a 3.5 year mean follow-up in ambulatory care in 45 French hospitals. The study included 631 male and female with diabetes aged 63.9 ± 5.1 years, with no evidence of coronary artery disease and at least 2 additional cardiovascular risk factors, receiving appropriate medical treatment. The patients were randomized centrally to either screening for silent ischemia using a bicycle exercise test or Dipyridamole Single Photon Emission Computed Tomography (N = 316), or follow-up without screening (N = 315). The main study end point was time to death from all causes, non-fatal myocardial infarction, non-fatal stroke, or heart failure requiring hospitalization or emergency service intervention. The results of a meta-analysis of DYNAMIT and DIAD, a similar study, are also presented. RESULTS: The study was discontinued prematurely because of difficulties in recruitment and a lower-than expected event rate. Follow-up was complete for 98.9% patients regarding mortality and for 97.5% regarding the main study end point. Silent ischemia detection procedure was positive or uncertain in 68 (21.5%) patients of the screening group. There was no significant difference between the screening and the usual care group for the main outcome (hazard ratio = 1.00 95%CI 0.59 to 1.71). The meta-analysis of these and DIAD results gave similar results, with narrower confidence intervals for each endpoint. CONCLUSIONS: These results suggest that the systematic detection of silent ischemia in high-risk asymptomatic patients with diabetes is unlikely to provide any major benefit on hard outcomes in patients whose cardiovascular risk is controlled by an optimal medical treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00627783.

[Nutrition approaches to prevent chronic disease]. / Prévention nutritionnelle des maladies chroniques.

Chronic diseases such as obesity, diabetes, macrovascular disease including coronaropathy and stroke, osteoporosis and various cancer have, in one way or another, food and nutritional determinants and may be considered as nutritionally or environmental-related diseases. There is a growing literature indicating that specific dietary constituents or diet are able to influence the development and the outcome of chronic disease. Long term prospective clinical trials are yet locking to confirm on evidences-based medicine criteria the correlation described between food and disease. However animal as well as epidemiological data suggest that high energy density and low nutrient density which characterized diet in developed countries are the main targets that must be fight. On the basis of current researches, Mediterranean diet seemed to be the best and the more applicable diet in order to have optimal health. Such a diet low in calories and saturated fat and high in fruit and vegetables and in whole grain should become a key composant for reduce the oxidant, inflammatory, atherogenic, mutagenic and hyperinsulinic status and then prevent or delay chronic diseases.

[Hyperglycemia in the critically ill: meaning and treatment]. / Hyperglycémie dans les maladies aiguës : signification et prise en charge.

Hyperglycemia is commun in critically ill patients without previously known diabetes. Hyperglycemia occurring in these patients is mainly a consequence of stress associated to complex glucose metabolism abnormalities which have deleterious effects on tissues and vascular function. Several epidemiologic and intervention studies had established that hyperglycemia is related to morbidity and mortality. Maintenance of normoglycemia with intensive insulin therapy seems to decrease morbidity and mortalities in severe acute illnesses. However the benefit of most of these intervention trials remain controversial mainly in stroke, myocardial infarction and severe sepsis. Moreover strict normoglycemia required to obtain an optimal benefit increases the risk of hypoglycaemia which may be particularly harmful in patients in critical state.