Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients with Familial Hypercholesterolemia: The ARCHITECT Study.

BACKGROUND: The effect of alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, on coronary plaque burden in patients with familial hypercholesterolemia has not been addressed. Our aim was to assess changes in coronary plaque burden and its characteristics after treatment with alirocumab by quantification and characterization of atherosclerotic plaque throughout the coronary tree on the basis of a noninvasive analysis of coronary computed tomographic angiography in asymptomatic subjects with familial hypercholesterolemia receiving optimized and stable treatment with maximum tolerated statin dose with or without ezetimibe. METHODS: This study is a phase IV, open-label, multicenter, single-arm clinical trial to assess changes in coronary plaque burden and its characteristics after 78 weeks of treatment with alirocumab in patients with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. Participants underwent an initial coronary computed tomographic angiography at baseline and another at 78 weeks. Every patient received 150 mg of alirocumab subcutaneiously every 14 days in addition to high-intensity statin therapy. The main outcome was the change on coronary plaque burden and its characteristics by quantification and characterization of atherosclerotic plaque throughout the coronary tree on the basis of analysis of coronary computed tomographic angiography. RESULTS: The study was completed by 104 patients. The median age was 53.3 (46.2-59.4) years. Of these patients, 54 were women (51.9%). Median low-density lipoprotein cholesterol was 138.9 (117.5-175.3) mg/dL at entry and 45.0 (36.0-65.0) mg/dL at follow-up (P<0.001). Coronary plaque burden changed from 34.6% (32.5%-36.8%) at entry to 30.4% (27.4%-33.4%) at follow-up (P<0.001). A significant change in the characteristics of the coronary atherosclerosis was also found: an increase in the proportion of calcified (+0.3%; P<0.001) and mainly fibrous (+6.2%; P<0.001) plaque, accompanied by a decrease in the percentage of fibro-fatty (-3.9%; P<0.001) and necrotic plaque (-0.6%; P<0.001). CONCLUSIONS: Treatment with alirocumab in addition to high-intensity statin therapy resulted in significant regression of coronary plaque burden and plaque stabilization on coronary computed tomographic angiography over 78 weeks in these groups of patients with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. ARCHITECT (Effect of Alirocumab on Atherosclerotic Plaque Volume, Architecture and Composition) could link and explain ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) results. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT05465278.

Sustained low-density lipoprotein-cholesterol <70 mg/dl is associated with improved cardiovascular outcomes in the clinical setting.

BACKGROUND AND AIMS: Clinical trials have shown that intensive low-density lipoprotein cholesterol (LDL-C) lowering improves cardiovascular outcomes among patients with atherosclerotic cardiovascular disease (ASCVD), but data are limited in real clinical practice, particularly for patients with ASCVD informing different territories. METHODS: FRENA was a prospective registry of consecutive outpatients with coronary, cerebrovascular or peripheral artery disease. We compared the incidence of recurrent events in patients with sustained LDL-C levels <70 mg/dl compared with those with ≥70 mg/dl. RESULTS: As of December 2018, 1182 patients were eligible for this study. Among them, 172 (14.5%) had mean LDL-C levels ≤70 mg/dl, and 1010 (85.5%) had <70 mg/dl. Their clinical characteristics at baseline were similar. During 5 years of follow-up, 252 patients (21%) suffered major adverse cardiovascular events (MACE). The incidence rates of MACE were 3.42 events per 100 patient-years (95% confidence interval [95% CI] 2.17-5.14) in patients with levels <70 mg/dl and 5.57 (95% CI, 4.87-6.34) in those with ≥70 mg/dl; the rate ratio was 0.61 (95% CI, 0.39-0.92), p = 0.019. On multivariable analysis, patients with LDL-C levels <70 mg/dl were at lower risk for MACE (hazard ratio [HR]: 0.61 [95% CI, 0.39-0.93] p < 0.05). MACE reduction was driven by a decrease in coronary and peripheral events with no significant effect on stroke. CONCLUSIONS: Long-term sustained LDL-C <70 mg/dl in the clinical practice is associated with reduction in cardiovascular and peripheral vascular events with no apparent effect on stroke.

Location of recurrent cardiovascular events and anticardiolipin antibodies.

BACKGROUND: The relationship between anticardiolipin (aCL) antibodies and cardiovascular events is uncertain and may vary according to arterial location. MATERIALS AND METHODS: FRENA is an ongoing registry of stable outpatients with symptomatic coronary artery disease (CAD), cerebrovascular disease (CVD) or peripheral artery disease (PAD). The rate of subsequent ischaemic events was cross-referenced with the presence of aCL antibodies (any isotype, IgG or IgM). RESULTS: As of June 2017, 1387 stable outpatients were recruited. Of these, 120 (8.7%) showed positive levels of aCL antibodies. Over an average follow-up of 18 months, 250 patients developed subsequent events: 101 myocardial infarction, 57 ischaemic stroke and 92 critical leg events. Patients with positive aCL antibodies had a higher risk of distal artery events (a composite of ischaemic stroke or critical leg events) than patients with undetectable or low levels (rate ratio: 1.66; 95% CI: 1.07-2.60). However, an association with central coronary events was not found. The multivariate Cox analysis after adjustment for relevant clinical covariates showed that positivity of aCL antibodies is an independent risk factor for distal events (hazard ratio: 1.60; 95% CI: 1.01-2.55; P < .05). CONCLUSIONS: Positivity of aCL antibodies is associated with an increased risk of subsequent distal artery ischaemic events (cerebral or leg arteries) but not coronary artery events. Anticardiolipin antibodies appear to have a different relationship on the localisation of ischaemic events in patients with symptomatic artery disease.

Improved lipid-lowering treatment and reduction in cardiovascular disease burden in homozygous familial hypercholesterolemia: The SAFEHEART follow-up study.

AIM: We aimed to describe clinical and genetic characteristics, lipid-lowering treatment and atherosclerotic cardiovascular disease (ASCVD) outcomes over a long-term follow-up in homozygous familial hypercholesterolemia (HoFH). METHODS: SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) is a long-term study in molecularly diagnosed FH. Data analyzed in HoFH were prospectively obtained from 2004 until 2022. ASCVD events, lipid profile and lipid-lowering treatment were determined. RESULTS: Thirty-nine HoFH patients were analyzed. The mean age was 42 ± 20 years and nineteen (49%) were women. Median follow-up was 11 years (IQR 6,18). Median age at genetic diagnosis was 24 years (IQR 8,42). At enrolment, 33% had ASCVD and 18% had aortic valve disease. Patients with new ASCVD events and aortic valve disease at follow-up were six (15%), and one (3%), respectively. Median untreated LDL-C levels were 555 mg/dL (IQ 413,800), and median LDL-C levels at last follow-up was 122 mg/dL (IQR 91,172). Most patients (92%) were on high intensity statins and ezetimibe, 28% with PCSK9i, 26% with lomitapide, and 23% with lipoprotein-apheresis. Fourteen patients (36%) attained an LDL-C level below 100 mg/dL, and 10% attained an LDL-C below 70 mg/dL in secondary prevention. Patients with null/null variants were youngers, had higher untreated LDL-C and had the first ASCVD event earlier. Free-event survival is longer in patients with defective variant compared with those patients with at least one null variant (p=0.02). CONCLUSIONS: HoFH is a severe life threating disease with a high genetic and phenotypic variability. The improvement in lipid-lowering treatment and LDL-C levels have contributed to reduce ASCVD events.

Characteristics of Coronary Atherosclerosis Related to Plaque Burden Regression During Treatment With Alirocumab: The ARCHITECT Study.

BACKGROUND: Intensive lipid-lowering therapy may induce coronary atherosclerosis regression. Nevertheless, the factors underlying the effect of lipid-lowering therapy on disease regression remain poorly characterized. Our aim was to determine which characteristics of atherosclerotic plaque are associated with a greater reduction in coronary plaque burden (PB) after treatment with alirocumab in patients with familial hypercholesterolemia. METHODS: The ARCHITECT study (Effect of Alirocumab on Atherosclerotic Plaque Volume, Architecture and Composition) is a phase IV, open-label, multicenter, single-arm clinical trial to assess the effect of the treatment with alirocumab for 78 weeks on the coronary atherosclerotic PB and its characteristics in subjects with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. Participants underwent a coronary computed tomographic angiography at baseline and a final one at 78 weeks. Every patient received alirocumab 150 mg subcutaneously every 14 days in addition to high-intensity statin therapy. RESULTS: One hundred and four patients were enrolled. Median age was 53.3 (46.2-59.4) years and 54 were women (51.9%). The global coronary PB changed from 34.6% (32.5%-36.8%) at entry to 30.4% (27.4%-33.4%) at follow-up, which is -4.6% (-7.7% to -1.9%; P<0.001) reduction. A decrease in the percentage of unstable core (fibro-fatty+necrotic plaque; from 14.1 [7.9-22.3] to 8.0 [6.4-10.6]; -6.6%; P<0.001) was found. A greater PB (ß, 0.36 [0.13-0.59]; P=0.002) and a higher proportion of unstable core (ß, 0.15 [0.08-0.22]; P<0.001) were significantly related to PB regression. CONCLUSIONS: Treatment with alirocumab in addition to high-intensity statin therapy might produce a greater PB regression in patients with familial hypercholesterolemia with higher baseline PB and in those with larger unstable core. Further studies are needed to corroborate the hypothesis raised by these results. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05465278.

Optimal Control of all Modifiable Vascular Risk Factors Among Patients With Atherosclerotic Disease. A Real-Life Study.

The effects of maintaining all classical, vascular risk factors on target among patients with stabilized atherosclerotic cardiovascular disease (ASCVD) are uncertain. Factores de Riesgo y ENfermedad Arterial (FRENA) was a prospective registry of consecutive outpatients with coronary, cerebrovascular, or peripheral artery disease. We analyzed the incidence of recurrent events and mortality according to sustained, optimal control of principal risk factors including the following: LDL cholesterol, glucose, blood pressure, and smoking. As of December 2018, 4285 stable outpatients were eligible for this study. Over a median follow-up of 21 months, 664 (15%) maintained all risk factors on target (Group 1), while 3621 (85%) did not (Group 2). During follow-up, no differences in recurrent major adverse cardiovascular events (MACEs) or death were observed between groups. On multivariable analysis, patients with previous known dyslipidemia (hazard ratio [HR]: 95% confidence interval (95% CI): ([HR]: 1.20 [95% CI, 1.03-1.40]), polyvascular disease ([HR]: 1.98 [95% CI, 1.69-2.32]), insulin therapy ([HR]: 1.56 [95% CI, 1.24-1.95]) and associated conditions ([HR]: 1.47 [95% CI, 1.24-1.74]) were associated with a higher risk for subsequent MACE. The presence of associated medical conditions was also strongly associated with all-cause death ([HR]: 3.49 [95% CI, 2.35-5.19]). Only a minority of patients with atherosclerotic cardiovascular disease achieved sustained optimal control for all principal risk factors although without discernible clinical, therapeutic benefit. The findings of the present study provide some insights into what factors may be used to guide physicians in adapting intensive, multifactorial therapy to the individual patient in clinical practice.

Association of Subclinical Carotid Atherosclerosis Assessed by High-Resolution Ultrasound With Traditional and Novel Anthropometric Indices.

Novel anthropometric indices have been proposed as an alternative to body mass index (BMI) and waist circumference (WC) to determine visceral adipose tissue and body mass. Little is known about the relationship of these new anthropometric indices to subclinical carotid atherosclerosis. The objective of this study was to assess the association of anthropometric indices, both new and traditional, with the presence of subclinical carotid artery arteriosclerosis (SCAA) estimated by Doppler ultrasound. This cross-sectional study analyzed 788 Spanish patients who consecutively attended a vascular risk consultation between June 2021 and September 2022. Traditional anthropometric indices (BMI, WHR and WHtR) and novel indices (ABSI, AVI, BAI, BRI, CI, CUNBAE and WWI) were calculated, and Doppler ultrasound in the carotid artery (cIMT and atherosclerosis plaque) was performed to detect SCAA. All analyzed anthropometric indices, except BMI, BAI and CUNBAE, were significantly higher in patients with SCAA. ABSI, BRI, CI, WHR, WHtR and WWI and were associated with SCAA in the univariate analysis (p<0.05); however, only ABSI (adjusted OR: 1.15; 95% CI: 1.10-2.38; p= 0.042) was significantly associated with SCAA in the multivariate analysis. In conclusion, only ABSI was significantly positively associated with SCAA, independent of other confounders.

Association between Asymptomatic Hyperuricemia with Adiposity Indices: A Cross-Sectional Study in a Spanish Population.

INTRODUCTION: New anthropometric indices have been developed as an alternative to body mass index (BMI) and waist circumference (WC) to assess body mass and visceral fat. Asymptomatic hyperuricemia is considered an independent cardiovascular risk factor. Currently, little is known about the relationship between asymptomatic hyperuricemia and several new anthropometric indices. This study aimed to assess the association between the presence of asymptomatic hyperuricemia and anthropometric indices, both novel and traditional. METHODS: This study analyzed 1094 Spanish subjects who consecutively visited the cardiovascular risk consultation of the University Hospital San Pedro de Alcántara of Cáceres, Spain, between June 2021 and September 2022. Anthropometric measures, including traditional and novel indices, were determined. The asymptomatic hyperuricemia group was defined according to serum uric acid levels. RESULTS: All the anthropometric indices studied, including new and traditional, were significantly greater among patients with asymptomatic hyperuricemia, except for WWI. In multiple linear regression analysis, serum uric acid levels were significantly correlated with BMI, WHR, WHtR, AVI, BAI, BRI, CUN-BAE, and WWI but not ABSI or CI. In the univariate analysis, all indices were associated with asymptomatic hyperuricemia (p < 0.05); however, only WHtR (adjusted OR: 2.93; 95% CI: 1.03-8.37; p = 0.044), AVI (adjusted OR: 1.46; 95% CI: 1.04-2.04; p = 0.026), and BRI (adjusted OR: 1.66; 95% CI: 1.19-2.32; p = 0.003) were significantly associated in multivariate analysis. Finally, WHtR, AVI, and BRI provided the largest AUCs. CONCLUSIONS: Our findings showed that WHtR, AVI, and BRI were independently positively associated with asymptomatic hyperuricemia and could be good predictors.

Metabolic Syndrome and Its Components in Patients with COVID-19: Severe Acute Respiratory Syndrome (SARS) and Mortality. A Systematic Review and Meta-Analysis.

Recent meta-analysis studies have reported that metabolic comorbidities such as diabetes, obesity, dyslipidaemia and hypertension are associated with higher risk of severe acute respiratory syndrome (SARS) and mortality in patients with COVID-19. This meta-analysis aims to investigate the relationship between metabolic syndrome (MetS) and its components with SARS and mortality in COVID-19 patients. METHODS: A systematic search was conducted in the several databases up until 1 September 2021. Primary observational longitudinal studies published in peer review journals were selected. Two independent reviewers performed title and abstract screening, extracted data and assessed the risk of bias using the Newcastle-Ottawa Scale. RESULTS: The random effects meta-analysis showed that MetS was significantly associated with SARS with a pooled OR (95% CI) of 3.21 (2.88-3.58) and mortality with a pooled OR (95% CI) of 2.32 (1.16-4.63). According to SARS, the pooled OR for MetS was 2.19 (1.71-2.67), p < 0.001; significantly higher than the hypertension component. With regard to mortality, although the pooled OR for MetS was greater than for its individual components, no significant differences were observed. CONCLUSIONS: this meta-analysis of cohort studies, showed that MetS is better associated to SARS and mortality in COVID-19 patients than its individual components.

Systolic Blood Pressure and Outcomes in Stable Outpatients with Recent Symptomatic Artery Disease: A Population-Based Longitudinal Study.

OBJECTIVES: The most appropriate targets for systolic blood pressure (SBP) levels to reduce cardiovascular morbidity and mortality in patients with symptomatic artery disease remain controversial. We compared the rate of subsequent ischemic events or death according to mean SBP levels during follow-up. DESIGN: Prospective cohort study. FRENA is an ongoing registry of stable outpatients with symptomatic coronary (CAD), cerebrovascular (CVD) or peripheral artery disease (PAD). SETTING: 24 Spanish hospitals. PARTICIPANTS: 4789 stable outpatients with vascular disease. RESULTS: As of June 2017, 4789 patients had been enrolled in different Spanish centres. Of these, 1722 (36%) had CAD, 1383 (29%) CVD and 1684 (35%) PAD. Over a mean follow-up of 18 months, 136 patients suffered subsequent myocardial infarction, 125 had ischemic stroke, 74 underwent limb amputation, and 260 died. On multivariable analysis, CVD patients with mean SBP levels 130-140 mm Hg had a lower risk of mortality than those with levels <130 mm Hg (hazard ratio (HR): 0.39; 95% CI: 0.20-0.77), as did those with levels >140 mm Hg (HR: 0.46; 95% CI: 0.26-0.84). PAD patients with mean SBP levels >140 mm Hg had a lower risk for subsequent ischemic events (HR: 0.57; 95% CI: 0.39-0.83) and those with levels 130-140 mm Hg (HR: 0.47; 95% CI: 0.29-0.78) or >140 mm Hg (HR: 0.32; 95% CI: 0.21-0.50) had a lower risk of mortality. We found no differences in patients with CAD. CONCLUSIONS: In this real-world cohort of symptomatic arterial disease patients, most of whom are not eligible for clinical trials, the risk of subsequent events and death varies according to the levels of SBP and the location of previous events. Especially among patients with large artery atherosclerosis, PAD or CVD, SBP <130 mm Hg may result in increased mortality. Due to potential factors in this issue, Prospective, well designed studies are warranted to confirm these observational data.

Effectiveness of Body Roundness Index (BRI) and a Body Shape Index (ABSI) in Predicting Hypertension: A Systematic Review and Meta-Analysis of Observational Studies.

INTRODUCTION: The body roundness index (BRI) and a body shape index (ABSI) are novel anthropometric indices established to determine both the amount visceral adipose tissue and body fat. OBJECTIVE: to investigate whether BRI and ABSI are better predictors of hypertension than body mass index (BMI), waist circumference (WC) or waist-to-height ratio (WHtR). Methods: A systematic search was conducted in the Scopus, PubMed and Web of Science databases up until 31 December 2020. RESULTS: The estimated pooled area under curve [AUC (95% CI)] for BRI [0.67 (0.65-0.70)] for the prediction of hypertension were superior to that of ABSI (0.58 (0.56-0.60)), similar to that of BMI [0.67 (0.64-0.69)], and lower than those WC [0.68 (0.66-0.70)] and WHtR [0.68 (0.66-0.71)]. Nevertheless, the difference of BRI compared to WC and WHtR in the context of predicting hypertension was non-significant. ABSI was significantly lower (p < 0.05) than BRI, BMI, WC and WHtR. Similar findings were observed with the summary receiver operating characteristic curve (AUC-SROC). There were no significant differences between subgroups according to type of population or diagnostic criteria of hypertension. The diagnostic odds ratio (dORs) proved that increased BRI and ABSI were related with an elevated hypertension risk. CONCLUSIONS: BRI and ABSI have discriminatory power for hypertension in adult women and men from different populations. Although, WHtR and WC provided the best performance when assessing hypertension, no significant differences were found for BRI. Finally, BRI was significantly better predictor of hypertension than ABSI.

Validation of the QMon-20 oscillometric blood pressure monitor for professional office use in the general population according to the ANSI/ESH/ISO 81060-2:2018 protocol.

OBJECTIVE: we assessed the accuracy of the QMon-20 oscillometric upper-arm cuff device professional for office blood pressure (BP) in general population according to the Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Universal Standard (ISO 81060-2:2018). METHODS: Subjects were recruited according to AAMI/ESH/ISO Universal Standard in general population using the same arm sequential BP measurement method. Two cuffs of the test device were used for arm circumference 22-31 (medium) and 32-42 cm (large). RESULTS: One-hundred and fourteen subjects were recruited and 106 were analyzed. For validation criterion 1, the mean ± SD of the differences between the test device and reference BP readings was 0.8 ± 5.4/-0.5 ± 4.2 mmHg (systolic/diastolic). For criterion 2, the SD of the mean BP differences between the test device and reference BP per subject was 4.34/3.48 mmHg (systolic/diastolic). CONCLUSION: The QMon-20 oscillometric device for office BPs measurement fulfilled all the requirements of the AAMI/ESH/ISO Universal Standard (ISO 81060-2:2018) in general population and can be recommended for clinical use.

Effectiveness of body roundness index in predicting metabolic syndrome: A systematic review and meta-analysis.

Body roundness index (BRI) is a new anthropometric index developed to predict both body fat and the percentage of visceral adipose tissue. Our aim was to investigate whether BRI is superior to traditional anthropometric indices in predicting metabolic syndrome (MetS). This systematic review and meta-analysis was conducted using Pubmed, Scopus and Web of Sciences databases. The estimated pooled areas under curve (AUCs) for BRI predicting MetS was higher than body mass index (BMI), waist-to-hip ratio (WHR), body shape index (ABSI) and body adiposity index (BAI), similar to waist circumference (WC) and lower than waist-to-height ratio (WHtR). However, the difference between BRI and BMI, WC and WHtR predicting MetS was statistically non-significant. Similar results were found with the summary receiver operating characteristic curve (AUC-SROC). In addition, the non-Chinese population had pooled AUCs greater than the Chinese population for all indices. Pooled ORs showed that BRI is associated with an increased MetS risk. In conclusion, BRI had good discriminatory power for MetS in adults of both sexes from diverse populations (AUC > 0.7; AUC-SROC>0.7). However, WC and WHtR offer the best performance when screening for MetS, and non-significant differences were found with BRI. In contrast, BRI was superior to BMI, WHR, ABSI and BAI in predicting MetS.

Cardio-ankle vascular index (CAVI) measured by a new device: protocol for a validation study.

INTRODUCTION: Cardio-ankle vascular index (CAVI) is a new marker of arterial stiffness (AS) that can assess vascular wall stiffness in the aorta, femoral artery and tibial artery. CAVI is less affected by blood pressure at the time of measurement than the gold standard method (carotid-femoral pulse wave velocity (PWV)). Our group has developed a device called VOPITB (Velocidad Onda de Pulso Índice Tobillo Brazo) that uses the oscillometric method and easily and accurately measures the PWV in the arms and legs separately, allowing new AS indices to be studied. This article describes the research protocol to determine CAVI using VOPITB and to validate the device against a reference device (VaSera VS-1500) and assess its clinical utility. METHODS AND ANALYSES: A cross-sectional, descriptive and observational study will be conducted. In all, 120 subjects (a minimum of 40% of subjects from any one gender) will be evaluated. CAVI will be determined from the measurement by VOPITB and VaSera VS-1500. For each subject, the average of the three readings taken with each device will be calculated. The Bland-Altman plot will be used to determine whether any bias exists in the data-that is, a tendency of the size of the difference to vary with the mean. The participants will be divided roughly equally between the following age bands: <30, 30-60 and >60 years. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee of the Hospital San Pedro de Alcántara, Cáceres, Spain. The participants will be required to sign an informed consent form before inclusion in the study, in accordance with the Declaration of Helsinki and WHO standards for observational studies. The dissemination plan of the research study results will be through presentations in relevant national and international conferences and scientific publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04303546.

Incidence of cardiovascular events and changes in the estimated risk and treatment of familial hypercholesterolemia: the SAFEHEART registry.

INTRODUCTION AND OBJECTIVES: The SAFEHEART study was designed to analyze the situation of familial heterozygous hypercholesterolemia (FHH) and improve knowledge of this disease in Spain. Our objective was to determine the incidence rate of cardiovascular events, the estimated risk of developing an event and its modification, the use of lipid-lowering treatment, and the achievement of low-density lipoprotein cholesterol targets in patients with FHH. METHODS: SAFEHEART is a prospective, open, multicenter, nationwide cohort study, with long-term protocol-based follow-up in a population of individuals with molecularly-characterized FHH. We analyzed patients older than 18 years with complete follow-up. RESULTS: We included 2648 patients with FHH. The median follow-up was 6.6 (4.8-9.7) years. The overall incidence rate of cardiovascular events was 1.3 events/100 patient-years. After the follow-up, the 10-year estimated risk of developing a cardiovascular event was reduced from 1.6% to 1.3% (P <.001). In the last follow-up, 20.6% and 22.2% of the patients in primary and secondary prevention achieved low-density lipoprotein cholesterol values <100mg/dL and <70mg/dL, respectively. CONCLUSIONS: This study was performed in the largest population of patients with FHH in Spain. We identified the incidence rate of cardiovascular events, the estimated risk of developing a cardiovascular event and its modification, the achievement of low-density lipoprotein cholesterol targets, and the therapeutic management in this population. Although the cardiovascular risk of FHH is high, appropriate treatment reduces the likelihood of an event. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Identifier: NCT02693548.

Long-term effect of 2 intensive statin regimens on treatment and incidence of cardiovascular events in familial hypercholesterolemia: The SAFEHEART study.

BACKGROUND: Maximal doses of potent statins are the basement of treatment of familial hypercholesterolemia (FH). Little is known about the use of different statin regimens in FH. OBJECTIVES: The objectives of the study were to describe the treatment changes and low-density lipoprotein cholesterol (LDL-C) goal achievement with atorvastatin (ATV) and rosuvastatin (RV) in the SAFEHEART cohort, as well as to analyze the incidence of atherosclerotic cardiovascular events (ACVEs) and changes in the cardiovascular risk. METHODS: SAFEHEART is a prospective follow-up nationwide cohort study in a molecularly defined FH population. The patients were contacted on a yearly basis to obtain relevant changes in life habits, medication, and ACVEs. RESULTS: A total of 1939 patients were analyzed. Median follow-up was 6.6 years (5-10). The estimated 10-year risk according the SAFEHEART risk equation was 1.61 (0.67-3.39) and 1.22 (0.54-2.93) at enrollment for ATV and RV, respectively (P < .001). There were no significant differences at the follow-up: 1.29 (0.54-2.82) and 1.22 (0.54-2.76) in the ATV and RV groups, respectively (P = .51). Sixteen percent of patients in primary prevention with ATV and 18% with RV achieved an LDL-C <100 mg/dL and 4% in secondary prevention with ATV and 5% with RV achieved an LDL-C <70 mg/dL. The use of ezetimibe was marginally greater in the RV group. One hundred sixty ACVEs occurred during follow-up, being its incidence rate 1.1 events/100 patient-years in the ATV group and 1.2 in the RV group (P = .58). CONCLUSION: ATV and RV are 2 high-potency statins widely used in FH. Although the reduction in LDL-C levels was greater with RV than with ATV, the superiority of RV for reducing ACVEs was not demonstrated.

Lipoprotein (a) levels and outcomes in stable outpatients with symptomatic artery disease.

BACKGROUND AND AIMS: Although genetic and epidemiological studies support that people with high lipoprotein (a) [Lp(a)] levels are at an increased risk for arterial disease, its prognostic value in patients with established artery disease has not been consistently evaluated. METHODS: FRENA is a prospective registry of consecutive outpatients with coronary, cerebrovascular or peripheral artery disease. We assessed the risk for subsequent myocardial infarction, ischemic stroke or limb amputation according to Lp(a) levels at baseline. RESULTS: As of December 2016, 1503 stable outpatients were recruited. Of these, 814 (54%) had levels <30 mg/dL, 319 (21%) had 30-50 mg/dL and 370 (25%) had ≥50 mg/dL. Over a mean follow-up of 36 months, 294 patients developed subsequent events (myocardial infarction 122, ischemic stroke 114, limb amputation 58) and 85 died. On multivariable analysis, patients with Lp(a) levels of 30-50 mg/dL were at a higher risk for myocardial infarction (hazard ratio [HR]: 4.67; 95%CI: 2.77-7.85), ischemic stroke (HR: 8.27; 95%CI: 4.14-16.5) or limb amputation (HR: 3.18; 95%CI: 1.36-7.44) than those with normal levels. Moreover, patients with levels ≥50 mg/dL were at increased risk for myocardial infarction (HR: 19.5; 95%CI: 10.5-36.1), ischemic stroke (HR: 54.5; 95%CI: 25.4-116.7) or limb amputation (HR: 22.7; 95%CI: 9.38-54.9). CONCLUSIONS: Stable outpatients with symptomatic artery disease and Lp(a) levels >30 mg/dL were at a 5-fold higher risk for subsequent myocardial infarction, stroke or limb amputation. Those with levels >50 mg/dL were at an over 10-fold higher risk.

Attainment of LDL-Cholesterol Treatment Goals in Patients With Familial Hypercholesterolemia: 5-Year SAFEHEART Registry Follow-Up.

BACKGROUND: Familial hypercholesterolemia (FH) is the most common genetic disorder associated with premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data on attainment of treatment targets; large registries that reflect real-life clinical practice can uniquely provide this information. OBJECTIVES: We sought to evaluate the achievement of low-density lipoprotein cholesterol (LDL-C) treatment goals in FH patients enrolled in a large national registry. METHODS: The SAFEHEART study (Spanish Familial Hypercholesterolemia Cohort Study) is a large, ongoing registry of molecularly defined patients with heterozygous FH treated in Spain. The attainment of guideline-recommended plasma LDL-C goals at entry and follow-up was investigated in relation to use of lipid-lowering therapy (LLT). RESULTS: The study recruited 4,132 individuals (3,745 of whom were ≥18 years of age); 2,752 of those enrolled were molecularly diagnosed FH cases. Mean follow-up was 5.1 ± 3.1 years; 71.8% of FH cases were on maximal LLT, and an LDL-C treatment target <100 mg/dl was reached by only 11.2% of patients. At follow-up, there was a significant increase in the use of ezetimibe, drug combinations with statins, and maximal LLT. The presence of type 2 diabetes mellitus, a defective allele mutation, ezetimibe use, and the absence of previous ASCVD were predictors of the attainment of LDL-C goals. CONCLUSIONS: Despite the use of intensified LLT, many FH patients continue to experience high plasma LDL-C levels and, consequently, do not achieve recommended treatment targets. Type of LDL-receptor mutation, use of ezetimibe, coexistent diabetes, and ASCVD status can bear significantly on the likelihood of attaining LDL-C treatment goals.

Statins do not increase the risk of developing type 2 diabetes in familial hypercholesterolemia: The SAFEHEART study.

BACKGROUND: Familial Hypercholesterolemia (FH) is the most common monogenic disorder that causes premature coronary artery disease (CAD). Our objective was to examine the risk of new onset type 2 diabetes mellitus (T2DM) among FH patients and unaffected relatives in relation to treatment with different statins in the SAFEHEART cohort study. METHODS: This is a cross-sectional and prospective cohort study in 2558 FH and 1265 unaffected relatives with a mean follow-up of 5.9 years. Several pertinent data, such as age, gender, metabolic syndrome, lipid profile, body mass index (BMI), waist circumference, HOMA-IR, dose, duration and type of statins, were obtained and examined as predictors of incident diabetes. RESULTS: The new onset diabetes was 1.7% in FH and 0.2% in non FH patients (p=0.001). In multivariate logistic regression, age (OR 1.02, CI 95%: 1.02-1.08), HOMA-IR (OR 1.17, CI 95%: 1.03-1.33), metabolic syndrome (OR 3.3, CI 95%: 1.32-8.28) and specifically plasma glucose, as a component of metabolic syndrome (OR 15.7, CI 95%: 4.70-52.53) were significant predictors of new onset T2DM in the FH group alone. In the adjusted Cox regression model in FH group, age (HR 1.03, CI 95% 1.00-1.06, p=0.031) and metabolic syndrome (HR 4.16, CI 95% 1.58-10.92, p=0.004) remained significant predictors of new onset T2DM. CONCLUSIONS: Our data do not support the postulated diabetogenic effect associated with high-dose statins use in our cohort of FH patients.

rs1801275 Interleukin-4 receptor alpha polymorphism in familial hypercholesterolemia.

BACKGROUND: Interleukin-4 (IL-4) has been linked with atherogenic effects and some single nucleotide polymorphisms (SNPs) of the IL4/13 receptors (ILR4/13) have been associated with enhanced response to IL-4. OBJECTIVES: We investigated the frequency of SNP ILR4/13 in patients with familial hypercholesterolemia (FH) compared with control relatives without FH and their possible association with cardiovascular disease (CVD). METHODS: ILR4/13 polymorphisms were studied in 626 subjects included in the Spanish FH cohort, 408 patients with FH and 218 healthy relative control subjects. Logistic regression was used to assess the relation between SNP, clinical data, and CVD. RESULTS: A total of 143 (35%) FH patients had rs1801275 polymorphisms (AG or GG) of the IL-4Rα, whereas only 52 (24%) of the control group had these polymorphisms, P = .002. No differences were observed between the groups when the IL13RA2 rs638376 polymorphisms were analyzed. The multivariate analysis found association (odds ratio: 95% confidence interval) between CVD and smoking history (2.22: 1.30-3.80), low levels of high-density lipoprotein cholesterol (1.72: 1.07-2.75), hypertension (2.25: 1.32-3.85), age > 60 years (2.50: 1.52-4.07), and FH diagnosis (13.1: 6.65-26), but not with IL-4Rα rs1801275 polymorphisms. CONCLUSION: Our data suggest that SNP of IL-4Rα is more frequent in FH patients than in the relative controls. Conversely to the general population, IL-4 does not seems to play a role in the risk of developing CVD in FH patients.