Physical signs and atherosclerotic cardiovascular disease in familial hypercholesterolemia: the HELLAS-FH Registry.

AIMS: Three physical signs, namely tendon xanthomas, corneal arcus and xanthelasma, have been associated with heterozygous familial hypercholesterolemia (heFH). The prevalence and clinical significance of these signs are not well established among contemporary heFH individuals. This study explored the frequency as well as the association of these physical signs with prevalent atherosclerotic cardiovascular disease (ASCVD) in heFH individuals. METHODS: Data from the Hellenic Familial Hypercholesterolemia Registry were applied for this analysis. The diagnosis of heFH was based on the Dutch Lipid Clinic Network Score. Multivariate logistic regression analysis was conducted to examine the association of heFH-related physical signs with prevalent ASCVD. RESULTS: Adult patients ( n  = 2156, mean age 50 ±â€Š15 years, 47.7% women) were included in this analysis. Among them, 14.5% had at least one heFH-related physical sign present. The prevalence of corneal arcus before the age of 45 years was 6.6%, tendon xanthomas 5.3%, and xanthelasmas 5.8%. Among physical signs, only the presence of corneal arcus before the age of 45 years was independently associated with the presence of premature coronary artery disease (CAD). No association of any physical sign with total CAD, stroke or peripheral artery disease was found. Patients with physical signs were more likely to receive higher intensity statin therapy and dual lipid-lowering therapy, but only a minority reached optimal lipid targets. CONCLUSION: The prevalence of physical signs is relatively low in contemporary heFH patients. The presence of corneal arcus before the age of 45 years is independently associated with premature CAD.

Obesity and atherosclerotic cardiovascular disease in adults with heterozygous familial hypercholesterolemia: An analysis from HELLAS-FH registry.

BACKGROUND: Familial hypercholesterolemia (FH) and obesity are well-established risk factors of atherosclerotic cardiovascular disease (ASCVD). Despite high prevalence, their joint association with ASCVD remains largely unknown. OBJECTIVE: To investigate the association of obesity with prevalent ASCVD in individuals with heterozygous FH (HeFH) enrolled in the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). METHODS: FH diagnosis was based on Dutch Lipid Clinic Network (DLCN) criteria. Adults with at least possible FH diagnosis (DLCN score ≥3) and available body mass index (BMI) values were included. Homozygous FH individuals were excluded. RESULTS: 1655 HeFH adults (mean age 51.0 ± 14.4 years, 48.6% female) were included; 378 (22.8%) and 430 (26.0%) were diagnosed with probable and definite FH, respectively. Furthermore, 371 participants (22.4%) had obesity and 761 (46.0%) were overweight. Prevalence of ASCVD risk factors increased progressively with BMI. Prevalence of coronary artery disease (CAD) was 23.4% (3.2% for stroke and 2.7% for peripheral artery disease, PAD), and increased progressively across BMI groups. After adjusting for traditional ASCVD risk factors and lipid-lowering medication, individuals with obesity had higher odds of established CAD (OR: 1.54, 95% CI: 1.04-2.27, p = 0.036) as well as premature CAD (OR: 1.74, 95% CI: 1.17-2.60, p = 0.009) compared with those with normal BMI. No association was found with stroke or PAD. CONCLUSIONS: Over half of adults with HeFH have overweight or obesity. Obesity was independently associated with increased prevalence of CAD in this population.

Evaluation of cardiovascular risk factors in children aged 6-16 years and their evolution in early adulthood in a 10-year follow-up study.

OBJECTIVE: Obesity and arterial hypertension (AH) in children represent well-recognized risk factors for cardiovascular (CV) events during adult life. We investigated any changes regarding several CV risk (CVR) factors in children after a 10-year follow-up period. METHODS: A cohort of 143 healthy children, elementary/high school students, 6-16 years old, was initially evaluated in 2010-2011 regarding CVR factors [obesity, blood pressure (BP), aortic stiffness (PWV), lipid profile] plus food habits/sports activity. At 10-years follow-up (2020-2021), 63/143 (44%) young adults were re-evaluated. RESULTS: Children with obesity (45%) had increased BP (p < 0.001) and a less favorable LDL-C/triglycerides profile (p = 0.001) compared to overweight/normoweight ones. In a 10-year follow-up, obesity and exercise improved (p < 0.001 and p = 0.005), systolic BP (SBP) (102 ± 13 vs. 118 ± 11 mmHg, p < 0.001) and PWV increased (6.1 ± 1 vs. 7.7 ± 1.1 m/sec, p < 0.001), LDL-C (96 ± 21 vs. 86 ± 24 mg/dl, p = 0.004) and HDL-C + (64 ± 18 vs. 55 ± 10 mg/dl, p < 0.001) decreased, triglycerides increased (62 ± 21 vs. 73 ± 34 mg/dl, p = 0.04), and food approached the western model of nutrition (less fish/fruits). In children/young adults, BMI was associated with age (Beta = 0.47, p < 0.001 and Beta = 0.36, p = 0.004), SBP (Beta = 0.46 and Beta = 0.52, p < 0.001), and LDL-C (Beta = 0.27 and Beta = 0.44, p < 0.001). CONCLUSIONS: In children with obesity, increased BMI and waist circumference were related to SBP and a less favorable lipid profile. At the 10-year re-evaluation, obesity was partially improved, physical activity was increased, and SBP had reached the high-normal levels in a substantial number of young adults, while lipid profile was less favorable (for HDL-C/triglycerides) compared to baseline evaluation. Our results highlight the evolution of CVR factors from childhood to early adulthood.

Investigating Non-Pharmacological Stress Reduction Interventions in Pediatric Patients Confirmed with Salivary Cortisol Levels: A Systematic Review.

For many children, hospitalization can lead to a state of increased anxiety. Being away from home, the invasive procedures undertaken, and the uncertainty of the outcome cause an uncomfortable situation in anticipation of real or imagined hazards. This systematic review aims to assess current evidence on the types of non-pharmacological interventions used and their impact on children's anxiety or distress levels when they visit the hospital for planned or unplanned admissions. The Databases PubMed, Psych INFO, and Google Scholar were queried for papers published from January 2000 to March 2023 reporting the use of non-pharmacological interventions interacting with children in hospital or clinical environments and confirmed with saliva cortisol levels. A total of nine studies were retrieved. Across these studies, four different strategies of non-pharmacological interventions were used. Anxiety and distress were found to be reduced in the majority of the studies as confirmed with salivary cortisol. Overall, there is evidence that non-pharmacological interventions hold a promising role in reducing levels of anxiety or distress in children as confirmed with saliva cortisol. However, research on saliva cortisol as a tool of anxiety measurement requires higher quality studies to strengthen the evidence base.

Measuring Children's Stress via Saliva in Surgical and Endoscopic Procedures and Its Measurement Intention in the Community: Reality-Future Prospects.

(1) Background: Children who undergo surgical or endoscopic procedures display high levels of stress, and various means are applied to reduce their anxiety. Salivary cortisol (S Cortisol) and salivary alpha-amylase (SAA) are often used as a valid biomarker of stress. The primary purpose of the study was the investigation of stress levels through S Cortisol and S amylase after intervention in surgical or endoscopic procedures (gastroscopy-colonoscopy). The secondary outcomes were the investigation of the intention to adopt new methods of saliva sampling. We collected saliva samples from children subjected to invasive medical procedures, with the aim of applying the Theory of Planned Behavior (TPB) as an intervention means to provide information and education to both parents and children undergoing stressful situations, and assess its efficacy in reducing stress levels. We also aimed at acquiring a better understanding of the acceptability of noninvasive biomarker collection in community settings. (2) Methods: The sample of this prospective study comprised 81 children who underwent surgical or endoscopic procedures at the Attikon General University Hospital, Athens, Greece and 90 parents. The sample was divided into two groups. The first, 'Group Unexplained', was not provided any information or education about the procedures, while the second, 'Group Explained', was informed and educated based on TPB. Thereafter, 8-10 weeks after intervention, the Theory of Planned Behavior questions were re-completed by the 'Group Explained'. (3) Results: Significant differences were detected in cortisol and amylase values between the two groups postoperatively after applying the TPB intervention. Saliva cortisol was reduced by 8.09 ng/mL in the 'Group Explained' while in the 'Group Unexplained' it was reduced by 4.45 ng/mL (p < 0.001). Salivary amylase values decreased by 9.69 ng/mL in the 'Group Explained' after the intervention phase of the study, while in the 'Group Unexplained' they increased by 35.04 ng/mL (p < 0.001). The regression explains 40.3% (baseline) and 28.5% (follow-up) of parental intention. The predictive factor of parental intention (baseline) is attitude (p < 0.001) and follow-up is behavioral control (p < 0.028) and attitude (p < 0.001). (4) Conclusions: Providing proper education and information for parents has a positive effect on reducing children's stress levels. Changing parental attitudes towards saliva collection plays the most important role, since a positive attitude can influence intention and ultimately participation in these procedures.

Prevalence of Diabetes and Its Association with Atherosclerotic Cardiovascular Disease Risk in Patients with Familial Hypercholesterolemia: An Analysis from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH).

Familial hypercholesterolemia (FH) and type 2 diabetes mellitus (T2DM) are both associated with a high risk of atherosclerotic cardiovascular disease (ASCVD). Little is known about the prevalence of T2DM and its association with ASCVD risk in FH patients. This was a cross-sectional analysis from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH) including adults with FH (n = 1719, mean age 51.3 ± 14.6 years). Of FH patients, 7.2% had a diagnosis of T2DM. The prevalence of ASCVD, coronary artery disease (CAD), and stroke was higher among subjects with T2DM compared with those without (55.3% vs. 23.3%, 48.8% vs. 20.7%, 8.3% vs. 2.7%, respectively, p < 0.001). When adjusted for age, systolic blood pressure, smoking, body mass index, hypertension, waist circumference, triglyceride levels, high-density lipoprotein cholesterol levels, and gender, T2DM was significantly associated with prevalent ASCVD [OR 2.0 (95% CI 1.2−3.3), p = 0.004]. FH patients with T2DM were more likely to have undergone coronary revascularization than those without (14.2% vs. 4.5% for coronary artery bypass graft, and 23.9% vs. 11.5% for percutaneous coronary intervention, p < 0.001). T2DM is associated with an increased risk for prevalent ASCVD in subjects with FH. This may have implications for risk stratification and treatment intensity in these patients.

LDL cholesterol target achievement in heterozygous familial hypercholesterolemia patients according to 2019 ESC/EAS lipid guidelines: Implications for newer lipid-lowering treatments.

BACKGROUND: The 2019 European guidelines (ESC/EAS) for the treatment of dyslipidaemias recommend more aggressive targets for low-density lipoprotein cholesterol (LDL-C) in patients with familial hypercholesterolemia (FH). Current lipid-lowering treatment is often inadequate to achieve these targets. METHODS: Data from the HELLAS-FH registry were analysed to assess achievement of LDL-C targets in adults with FH based on the 2019 ESC/EAS guidelines. In patients who had not achieved LDL-C target, the maximally reduced LDL-C value was calculated after theoretical switch to rosuvastatin/ezetimibe 40/10 mg/day. The percentage of patients who remained candidates for proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) was then calculated. RESULTS: Patients (n = 1694, mean age 50.8 ± 14.7 years) had LDL-C levels 242 ± 71 mg/dL (6.3 ± 1.8 mmol/L) at diagnosis. Most treated patients were receiving statins (97.5%) and about half were on additional ezetimibe (47.5%). Based on the 2019 ESC/EAS guidelines the percentage of patients achieving LDL-C goals was only 2.7%. Following theoretical up titration to rosuvastatin/ezetimibe 40/10 mg, LDL-C target achievement rate would increase to 5.9%. In this scenario, most patients (55.9%) would be eligible for PCSK9i treatment. Following theoretical administration of a PCSK9i, LDL-C target achievement rate would rise to 57.6%. However, 42.4% of patients would still be eligible for further LDL-C lowering treatment. CONCLUSIONS: Most FH patients do not reach new LDL-C targets even if on maximum intensity statin/ezetimibe treatment. In this case, more than half of FH patients are candidates for PCSK9i therapy and a considerable proportion may still require additional LDL-C lowering.

The Effect of Long-Term Atorvastatin Therapy on Carotid Intima-Media Thickness of Children With Dyslipidemia.

Carotid intima-media thickness (cIMT) has been proposed as an early marker of subclinical atherosclerosis in high risk children. Children with heterozygous familial hypercholesterolemia have greater cIMT than matched healthy controls or their unaffected siblings. Statin therapy may delay the progression of cIMT, although long-term studies in children are scarce. We evaluated the effect of atorvastatin treatment on cIMT in children with dyslipidemia. We studied 81 children/adolescents, 27 with severe dyslipidemia (low-density lipoprotein cholesterol [LDL-C] ≥190 mg/dL) and 54 sex- and age-matched healthy controls; LDL-C ≤ 130 mg/dL and lipoprotein (a), Lp(a), ≤30 mg/dL. In the children with dyslipidemia, cIMT was measured twice, before and on treatment (18.2 ± 7.7 months). Anthropometric data, a full lipid profile, liver, kidney, and thyroid function were evaluated. Males with dyslipidemia had a greater cIMT than male controls after adjustment for other factors (P = .049). In addition, a nonstatistically significant decrease in cIMT was observed after treatment (P = .261). Treatment with atorvastatin resulted in a significantly improved lipid profile. Females with dyslipidemia had a significantly thinner cIMT than males. Children with normal and high Lp(a) levels had similar cIMT values. In conclusion, treatment with atorvastatin had a beneficial effect on the lipid profile and cIMT progression in children with severe dyslipidemia.

Achieving low-density lipoprotein cholesterol targets as assessed by different methods in patients with familial hypercholesterolemia: an analysis from the HELLAS-FH registry.

BACKGROUND: Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and increased cardiovascular disease (CVD) risk. FH patients often have increased lipoprotein(a) [Lp(a)] levels, which further increase CVD risk. Novel methods for accurately calculating LDL-C have been proposed. METHODS: Patients with FH were recruited by a network of Greek sites participating in the HELLAS-FH registry. LDL-C levels were calculated using the Friedewald (LDL-CF) and the Martin/Hopkins (LDL-CM/H) equations as well as after correcting LDL-CM/H for Lp(a) levels [LDL-CLp(a)corM/H]. The objective was to compare LDL-C levels and target achievement as estimated by different methods in FH patients. RESULTS: This analysis included 1620 patients (1423 adults and 197 children). In adults at diagnosis, LDL-CF and LDL-CM/H levels were similar [235 ± 70 mg/dL (6.1 ± 1.8 mmol/L) vs 235 ± 69 mg/dL (6.1 ± 1.8 mmol/L), respectively; P = NS], while LDL-CLp(a)corM/H levels were non-significantly lower than LDL-CF [211 ± 61 mg/dL (5.5 ± 1.6 mmol/L); P = 0.432]. In treated adults (n = 966) both LDL-CF [150 ± 71 mg/dL (3.9 ± 1.8 mmol/L)] and LDL-CM/H levels [151 ± 70 mg/dL (6.1 ± 1.8 mmol/L); P = 0.746] were similar, whereas LDL-CLp(a)corM/H levels were significantly lower than LDL-CF [121 ± 62 mg/dL (3.1 ± 1.6 mmol/L); P < 0.001]. Target achievement as per latest guidelines in treated patients using the LDL-CM/H (2.5%) and especially LDL-CLp(a)corM/H methods (10.7%) were significantly different than LDL-CF (2.9%; P < 0.001). In children, all 3 formulas resulted in similar LDL-C levels, both at diagnosis and in treated patients. However, target achievement by LDL-CF was lower compared with LDL-CM/H and LDL-CLp(a)corM/H methods (22.1 vs 24.8 vs 33.3%; P < 0.001 for both comparisons). CONCLUSION: LDL-CLp(a)corM/H results in significantly lower values and higher target achievement rate in both treated adults and children. If validated in clinical trials, LDL-CLp(a)corM/H may become the method of choice to more accurately estimate 'true' LDL-C levels in FH patients.

Antiphospholipid and Antinuclear Antibodies in Children with Idiopathic Epilepsy: A 2-Year Prospective Study.

BACKGROUND AND PURPOSE: The high prevalence of antiphospholipid antibodies (aPL) and antinuclear antibodies (ANA) in patients with epilepsy may be associated with either the disease itself or the antiepileptic treatment. The purpose of this prospective study was to determine the prevalence of aPL and ANA in children with idiopathic epilepsy before and during treatment with antiepileptic drugs. METHODS: aPL, including both anticardiolipin and anti-ß2-glycoprotein I antibodies, and ANA statuses were determined in 40 healthy children, 30 children treated with sodium valproate (VPA) monotherapy, and 20 children treated with carbamazepine (CBZ) monotherapy before and at 6, 12, and 24 months after treatment initiation. RESULTS: Fifteen children (50%) in the VPA-treated group and 7 (35%) in the CBZ-treated group showed positivity for aPL before treatment initiation, compared with only 4 of the 40 controls. Nine children (30%) in the VPA-treated group and 4 (20%) in the CBZ-treated group showed positivity for ANA before treatment initiation, compared with only 2 of the 40 controls. The subgroup analysis found nonsignificant associations at the different time points regarding the positivity of all of the autoantibodies. Only patients treated with VPA had a significantly decreased risk of aPL positivity after 6 months of treatment. CONCLUSIONS: The increased prevalence of autoantibodies in children with idiopathic epilepsy is strongly associated with the disease itself.

Effect of levetiracetam monotherapy on lipid profiles and thyroid hormones in children with epilepsy: A prospective study.

Long-term treatment with some older antiepileptic drugs may lead to dyslipidemia or thyroid disturbances. The effect of levetiracetam (LEV), a newer broad spectrum antiepileptic agent, on cardiovascular risk factors is not yet sufficiently investigated. The purpose of this study was to investigate prospectively the effect of LEV monotherapy on serum lipid profile and thyroid hormones levels in children with epilepsy. The study population consisted of 39 children (21 females, 18 males, mean age 6.8 ± 4,1 years, range 2-15 years) that were treated for new-onset epilepsy with LEV monotherapy. Serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), apolipoprotein A-I (apo A-I), apolipoprotein B (apo B), lipoprotein (a) [Lp(a)], thyroxine (T4), free thyroxine (FT4) and thyrotropin (TSH), were evaluated before and at 6 and 12 (n = 28) months of LEV monotherapy. TGs were significantly decreased at 6 and 12 months of LEV treatment (p = 0.026 and p = 0.001, respectively). TGs/HDL-C ratio was significantly decreased at 6 and 12 months of LEV treatment (p = 0.024 and p = 0.003, respectively), while LDL-C/HDL-C ratio was significantly decreased at 12 months of LEV treatment (p = 0.025). There were no significant alterations in the other parameters during the study. In conclusion, long-term LEV monotherapy does not cause adverse alterations on thyroid hormones and serum lipids in children with epilepsy. More studies are needed to clarify whether LEV monotherapy have a favourable effect on serum lipids and whether LEV may be considered as a safer alternative drug for the prevention of antiepileptic drug-induced cardiovascular complications in adult life.

Short-Term and Long-Term Effects of Levetiracetam Monotherapy on Homocysteine Metabolism in Children with Epilepsy: A Prospective Study.

BACKGROUND AND PURPOSE: Long-term treatment with some older antiepileptic drugs may lead to hyperhomocysteinemia. Levetiracetam (LEV) is a newer broad-spectrum antiepileptic agent whose effects on homocysteine concentrations remain unclear. The purpose of this study was to prospectively determine the short-term and long-term effects of LEV monotherapy on homocysteine metabolism in children with epilepsy. METHODS: The study population consisted of 32 children [18 females, 14 males; age 5.94±4.10 years (mean±SD), age range 1-15 years] who received LEV monotherapy for new-onset epilepsy. Serum folate, serum vitamin B12, and plasma total homocysteine (p-tHcy) were measured before and at 2 months (n=32), 6 months (n=25), and 12 months (n=18) of LEV monotherapy. RESULTS: p-tHcy was significantly decreased at 2 months of treatment (p=0.031). Furthermore, analysis of covariance showed statistically significant decreases in p-tHcy at 2 months (p=0.013) and 6 months (p=0.015) of LEV treatment after controlling for age, sex, body mass index, and LEV dose. There were no significant alterations in the other parameters during the study. The drug doses were 18.1±7.1, 20.1±9.2, and 21.2±11.8 mg/kg at 2, 6, and 12 months of LEV treatment, respectively. CONCLUSIONS: In contrast with older antiepileptic drugs, long-term LEV monotherapy in children with epilepsy does not cause adverse alterations on homocysteine metabolism. Larger prospective studies are needed to definitively clarify whether LEV may be considered a safer alternative drug for preventing antiepileptic-drug-induced cardiovascular complications in adult life.

Hypovitaminosis D in Healthy Pregnant Women and their Newborns in Greece.

BACKGROUND/OBJECTIVES: The aim of this work was to evaluate the current vitamin D status in healthy pregnant women and their newborns living in Greece and assess possible associations between 25(OH)D and anthropometric features of their fetuses and newborns. MATERIALS & METHODS: 81 healthy women were monitored during pregnancy. Biochemical markers related to bone metabolism, 25(OH)D and PTH levels were measured in serum samples of mothernewborn pairs at 1st trimester of pregnancy and at delivery in mothers, in cord blood and at the 3rd day of life of newborns. RESULTS: Maternal 25(OH)D levels at the 1st trimester of pregnancy (22.6±9.2ng/ml) were significantly higher than those at delivery (19.2±9.2ng/ml) (p<0.001). Furthermore, umbilical 25(OH)D levels (21.3±9.3ng/ml) were higher than maternal at delivery (p=0.005) and neonatal levels (19.4±10.4 ng/ml) (p=0.021). Only 57.3% of the mothers at the first trimester and 46.7% at delivery as well as 55.8% of the fetuses and 38.5% of the neonates had adequate vitamin D levels (25(OH)D≥30ng/ml). A significant positive correlation was found between fetal femur length at the 22nd week of gestation and maternal 25(ΟΗ)D at the 1st trimester of pregnancy (r=0.36, p=0.048) while body length was significantly higher in newborns whose mothers had sufficient 25(OH)D levels (51.5±2.1cm) compared with those whose mothers had insufficient or deficient 25(OH)D levels at delivery (50.6±2.0cm) (p=0.047). CONCLUSION: The study confirms inadequate levels of vitamin D in pregnant women in Greece associated with inadequate vitamin D levels of their fetuses and newborns.