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.

Persistence with long-term PCSK9 inhibitor treatment and its effectiveness in familial hypercholesterolaemia: data from the SAFEHEART study.

AIMS: Most heterozygous familial hypercholesterolaemia (FH) patients require intensive lipid-lowering therapy (LLT) including PCSK9 inhibitors (PCSK9is) to reach current low-density lipoprotein cholesterol (LDL-C) goals. Persistence with chronic treatment is important to reduce the burden of atherosclerotic cardiovascular disease. We analysed persistence, efficacy, and impact on quality of life (QoL) of PCSK9i in FH patients in clinical practice setting. METHODS AND RESULTS: Spanish Familial Hypercholesterolaemia Cohort Study (SAFEHEART) is an open, prospective study in genetically defined FH patients in Spain. Patients ≥18 years of age (n = 696, 46% females) on stable LLT treated with PCSK9i were analysed. Median LDL-C at starting PCSK9i was 145 mg/dL [interquartile range (IQR), 123-177], 3.8 mmol/L (IQR 3.2-4.6). After a median follow up of 3.7 years (IQR 2.3-4.8), 27 patients (4%) discontinued PCSK9i treatment: 5 temporarily (0.7%) and 22 permanently (3.2%). Persistence with PCSK9i was 96.1% in the whole period. Median LDL-C levels and % LDL-C reduction attained after 1 year of treatment and in the last follow-up visit were 63 mg/dL (IQR 43-88), 1.6 mmol/L (IQR 1.1-2.23); 61 mg/dL (IQR 44-82), 1.6 mmol/L (IQR 1.1-2.1); 57.6% (IQR 39.5-69); and 58% (IQR 44-68), respectively. 2016 and 2019 ESC/EAS LDL-C goals were attained by 77 and 48% of patients, respectively, at the last follow-up visit (P < 0.001). Mean QoL score increased slightly in the first year and remained stable. CONCLUSION: Long-term persistence with PCSK9i in FH patients is very high, with a good QoL. Effectiveness in LDL-C reduction and LDL-C goal achievement dramatically improved with PCSK9i in this high-risk population in clinical practice setting. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02693548.

Efficacy of PCSK9 inhibitors in the treatment of heterozygous familial hypercholesterolemia: A clinical practice experience.

BACKGROUND: PCSK9 inhibitors are a treatment option for patients with familial hypercholesterolemia not on low-density lipoprotein cholesterol goals despite the use of maximally tolerated high intensity-statins dose. OBJECTIVE: To evaluate the efficacy of alirocumab and evolocumab in LDL-C reduction and targets attainment in patients with heterozygous familial hypercholesterolemia in clinical practice setting. METHODS: SAFEHEART is an open, long-term prospective study of a cohort of subjects with molecular diagnosis of familial hypercholesterolemia. This study analyze subjects ≥ 20 years of age on stable lipid-lowering therapy, who received PCSK9 inhibitors during the period 2016 to January 2020. RESULTS: 433 patients (mean age 55 years, 53% male, 39% with cardiovascular disease) were included and followed-up for a median of 2.5 years (IQR 1.6-3.0). Median LDL-C level prior to PCSK9 inhibitors was 145 mg/dL (IQR 125-173). The addition of PCSK9 inhibitors (211 alirocumab, 222 evolocumab) reduced LDL-C by 58% (IQR 41-70) p<0.001, in men and women, achieving a median LDL-C level of 62 mg/dL (IQR 44-87) without differences between both PCSK9 inhibitors. Out of them 67% with and 80% without cardiovascular disease reached 2016 ESC/EAS LDL-C targets, and 46% very high risk and 50% high risk patients achieved 2019 ESC/EAS LDL-C goals. Independent predictor factors for attainment of 2019 ESC/EAS LDL-C goals were to be male, smoking and the use of statins with ezetimibe. Both inhibitors were well tolerated. CONCLUSIONS: PCSK9 inhibitors on top of maximum lipid-lowering treatment significantly reduced LDL-C levels in patients with familial hypercholesterolemia and improved the achievement of LDL-C targets.

Lipoprotein(a), LDL-cholesterol, and hypertension: predictors of the need for aortic valve replacement in familial hypercholesterolaemia.

AIMS: Familial hypercholesterolaemia (FH) and elevated lipoprotein(a) [Lp(a)] are inherited disorders associated with premature atherosclerotic cardiovascular disease (ASCVD). Aortic valve stenosis (AVS) is the most prevalent valvular heart disease and low-density lipoprotein cholesterol (LDL-C) and Lp(a) may be involved in its pathobiology. We investigated the frequency and predictors of severe AVS requiring aortic valve replacement (AVR) in molecularly defined patients with FH. METHODS AND RESULTS: SAFEHEART is a long-term prospective cohort study of a population with FH and non-affected relatives (NAR). We analysed the frequency and predictors of the need for AVR due to AVS in this cohort. Five thousand and twenty-two subjects were enrolled (3712 with FH; 1310 NAR). Fifty patients with FH (1.48%) and 3 NAR (0.27%) required AVR [odds ratio 5.71; 95% confidence interval (CI): 1.78-18.4; P = 0.003] after a mean follow-up of 7.48 (3.75) years. The incidence of AVR was significantly higher in patients with FH (log-rank 5.93; P = 0.015). Cox regression analysis demonstrated an association between FH and AVR (hazard ratio: 3.89; 95% CI: 1.20-12.63; P = 0.024), with older age, previous ASCVD, hypertension, increased LDL-CLp(a)-years, and elevated Lp(a) being independently predictive of an event. CONCLUSION: The need for AVR due to AVS is significantly increased in FH patients, particularly in those who are older and have previous ASCVD, hypertension, increased LDL-CLp(a)-years and elevated Lp(a). Reduction in LDL-C and Lp(a) together with control of hypertension could retard the progression of AVS in FH, but this needs testing in clinical trials.ClinicalTrials.gov number NCT02693548.

Coronary plaque burden, plaque characterization and their prognostic implications in familial hypercholesterolemia: A computed tomographic angiography study.

BACKGROUND AND AIMS: Heterozygous familial hypercholesterolemia (FH) is associated with premature atherosclerotic cardiovascular disease. Semi-automated plaque characterization (SAPC) by coronary computed tomographic angiography (CTA) provides information regarding coronary plaque burden and plaque characterization. Our aim was to quantify and characterize the coronary plaque burden of patients with FH using SAPC analysis and to identify which factors are related to plaque burden and plaque characteristics. A second aim was to analyse the prognostic implications of these parameters. METHODS: Two hundred and fifty-nine asymptomatic individuals with molecularly determined FH were enrolled in this follow-up cohort study and underwent a coronary CTA analysed with SAPC. RESULTS: Mean follow-up time after coronary CTA was 3.9 ± 2 years. Mean age was 46.9 (10.7) years (130 women, 50.2%). Median plaque burden was 25.0% (19.0-29.0), non-calcified plaque burden 22.83% (17.94-26.88), calcified plaque-burden 1.12% (0.31-2.86) and CCS 8.9 (0-93). Five-year risk was independently related to plaque burden, non-calcified plaque burden, calcified plaque burden and coronary calcium score (B:3.75, 95%CI:2.92-4.58; p < 0.001, B:2.9, 95%CI:2.15-3.66; p < 0.001, B:0.75, 95%CI 0.4-1.1; p < 0.001 and B:82.2, 95%CI:49.28-115.16; p < 0.001 respectively). During follow-up, there were 15 (5.81%) nonfatal events and 1 (0.4%) fatal event. Plaque burden was significantly related to event-free survival during follow-up (HR:1.11; 95%CI:1.05-1.18; p < 0.001). CONCLUSIONS: Coronary atherosclerosis and its qualitative components may be quantified by means of SAPC in patients with FH. Plaque burden, calcified plaque burden and non-calcified plaque burden were independently related to the estimated cardiovascular risk. Plaque burden was also related to prognosis.

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.

Coronary computed tomographic angiography findings and their therapeutic implications in asymptomatic patients with familial hypercholesterolemia. Lessons from the SAFEHEART study.

BACKGROUND: Familial hypercholesterolemia (FH) confers an increased risk of premature atherosclerotic disease. Coronary computed tomographic angiography (CTA) can assess preclinical coronary atherosclerosis. OBJECTIVES: To describe coronary CTA findings in asymptomatic molecularly defined FH individuals, to identify those factors related to its presence and extension, and to assess the impact of these results in patients' care and estimated risk. METHODS: Four hundred and forty individuals with FH, without clinical cardiovascular disease, were consecutively enrolled and underwent a coronary CTA that was used to analyze coronary atherosclerosis based on coronary calcium score (CCS), sum of stenosis severity, and plaque composition sum (PCS). For FH patients, cardiovascular risk was estimated using the specific SAFEHEART risk equation. Follow-up was performed using a standardized protocol. RESULTS: Mean age was 46.4 years (231 women, 52%). Coronary calcium was present in 55%, mean CCS was 130.9, 46% had a plaque with lumen involvement, and mean PCS was 1.1. During follow-up, there were 17 (4%) nonfatal events and 2 (1%) fatal events. CCS was independently associated to the estimated risk and low-density lipoprotein-cholesterol life-years, sum of stenosis severity to the estimated risk, and PCS to the estimated risk and low-density lipoprotein-cholesterol life-years. CTA findings induced a positive change in patients' care and in their estimated risk. CONCLUSION: Coronary artery atherosclerosis is highly prevalent in asymptomatic patients with FH and it is independently associated to cardiovascular risk. More advanced disease on CTA was associated with subsequent intensification of therapy and reduction of estimated risk. Further longitudinal studies are required to know if these findings might improve the risk stratification in patients with FH.

Predicting Cardiovascular Events in Familial Hypercholesterolemia: The SAFEHEART Registry (Spanish Familial Hypercholesterolemia Cohort Study).

BACKGROUND: Although risk factors for atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolemia (FH) have been described, models for predicting incident ASCVD have not been reported. Our aim was to use the SAFEHEART registry (Spanish Familial Hypercholesterolemia Cohort Study) to define key risk factors for predicting incident ASCVD in patients with FH. METHODS: SAFEHEART is a multicenter, nationwide, long-term prospective cohort study of a molecularly defined population with FH with or without previous ASCVD. Analyses to define risk factors and to build a risk prediction equation were developed, and the risk prediction equation was tested for its ability to discriminate patients who experience incident ASCVD from those who did not over time. RESULTS: We recruited 2404 adult patients with FH who were followed up for a mean of 5.5 years (SD, 3.2 years), during which 12 (0.5%) and 122 (5.1%) suffered fatal and nonfatal incident ASCVD, respectively. Age, male sex, history of previous ASCVD, high blood pressure, increased body mass index, active smoking, and low-density lipoprotein cholesterol and lipoprotein(a) levels were independent predictors of incident ASCVD from which a risk equation with a Harrell C index of 0.85 was derived. The bootstrap resampling (100 randomized samples) of the original set for internal validation showed a degree of overoptimism of 0.003. Individual risk was estimated for each person without an established diagnosis of ASCVD before enrollment in the registry by use of the SAFEHEART risk equation, the modified Framingham risk equation, and the American College of Cardiology/American Heart Association ASCVD Pooled Cohort Risk Equations. The Harrell C index for these models was 0.81, 0.78, and 0.8, respectively, and differences between the SAFEHEART risk equation and the other 2 were significant (P=0.023 and P=0.045). CONCLUSIONS: The risk of incident ASCVD may be estimated in patients with FH with simple clinical predictors. This finding may improve risk stratification and could be used to guide therapy in patients with FH. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT02693548.

Attainment of LDL Cholesterol Treatment Goals in Children and Adolescents With Familial Hypercholesterolemia. The SAFEHEART Follow-up Registry.

INTRODUCTION AND OBJECTIVES: Little is known about the characteristics of persons with familial hypercholesterolemia (FH) younger than 18 years, the lipid-lowering therapy used in these patients, and the lipid goals reached in real life. Our aim was to evaluate the achievement of low-density lipoprotein cholesterol (LDL-C) treatment goals in FH patients younger than 18 years enrolled in a large national registry. METHODS: We analyzed patients younger than 18 years enrolled in a large ongoing registry of molecularly-defined patients with FH in Spain. The attainment of guideline-recommended plasma LDL-C goals at entry and follow-up was analyzed in relation to the use of lipid-lowering therapy. RESULTS: We enrolled 392 individuals younger than 18 years. Of these, 217 were molecularly-diagnosed FH patients and had a complete follow-up. The median follow-up time was 4.69 years (interquartile range, 2.48-6.38 years), 68.2% of FH patients were on statins, and 41.5% patients had LDL-C < 130mg/dL. Statin use was the only predictor of LDL-C goal attainment. CONCLUSIONS: This study shows that a high proportion of FH patients younger than 18 years have high LDL-C levels and fail to achieve recommended LDL-C targets. Statin use was the only independent predictor of LDL-C goal achievement. No safety concerns were detected during follow-up. These results indicate that many FH patients are not adequately controlled and that there is still room for treatment improvement.

Clinical and molecular characteristics of homozygous familial hypercholesterolemia patients: Insights from SAFEHEART registry.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder associated with very high levels of cholesterol, accelerated atherosclerosis and very premature death, often secondary to occlusion of the coronary ostia by supravalvular atheroma in untreated individuals. OBJECTIVE: To describe molecular and clinical characteristics of HoFH enrolled at SAFEHEART registry and to evaluate the role of the type of mutation in clinical expression. METHODS: SAFEHEART is a registry of molecularly defined familial hypercholesterolemia patients. A standardized phone call is made every year for the follow-up. Patients with confirmed HoFH were selected. Molecular and clinical characteristics were analyzed. RESULTS: Thirty-four HoFH patients (27 true HoFH, 4 compound heterozygous familial hypercholesterolemia, and 3 autosomal recessive hypercholesterolemia) have been enrolled in the period 2004-2015. Twenty different mutations in LDLR gene have been detected. Sixteen patients carry defective mutations (DMs), and 15 carry null mutations (NMs). Only patients with NMs met low-density lipoprotein cholesterol (LDL-C) criteria for clinical diagnosis. Patients with NMs had higher untreated LDL-C levels (P < .0001), more aortic valve stenosis (P < .05), and lower age at first cardiovascular event (P < .05) compared to patients with DMs. In the follow-up, 1 liver transplant patient died and 3 cases underwent revascularization procedures. Eight cases started LDL apheresis and 1 case had a liver transplant. CONCLUSIONS: HoFH phenotypic expression is highly variable. These patients have high atherosclerotic coronary artery disease risk including aortic valve stenosis and do not achieve the LDL-C treatment goals with standard therapy.

Coronary Heart Disease, Peripheral Arterial Disease, and Stroke in Familial Hypercholesterolaemia: Insights From the SAFEHEART Registry (Spanish Familial Hypercholesterolaemia Cohort Study).

OBJECTIVE: Heterozygous familial hypercholesterolemia (FH) is the most common premature atherosclerotic cardiovascular disease (ASCVD)-related monogenic disorder, and it is associated with ischemic heart disease. There is limited information whether FH increases the risk of peripheral arterial and cerebrovascular disease. Our aim was to analyze ASCVD prevalence and characteristics in different arterial territories in a large FH population, to compare them with an unaffected control population and to determine which factors are associated to ASCVD. APPROACH AND RESULTS: SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) is an ongoing registry of molecularly defined patients with heterozygous FH in Spain. ASCVD in the different arterial territories was analyzed, as well as individual characteristics, genetic variables, and lipid-lowering therapies. The study recruited 4132 subjects (3745 ≥18 years); 2,752 of those enrolled were molecularly diagnosed FH cases. Median age was 44.0 years (45.9% men) and 40 years (46.6% men) in FH patients and unaffected relatives (P<0.001). ASCVD was present in 358 (13.0%) and 47 (4.7%) FH patients and unaffected relatives, respectively (P<0.001). History of premature ASCVD was more prevalent in FH patients (9.4% and 2.4% in FH patients and unaffected relatives, respectively; P<0.001). Coronary artery-related manifestations and peripheral artery disease were more prevalent in FH patients than in controls, but no significant differences were found for cerebrovascular events. Age, body mass index, type 2 diabetes mellitus, high blood pressure, previous use of tobacco, and lipoprotein(a) >50 mg/dL were independently associated with ASCVD. CONCLUSIONS: The prevalence of ASCVD is higher, and the involvement of the arterial territories is different in FH patients when compared with their unaffected relatives. Age, male sex, increased body mass index, hypertension, type 2 diabetes mellitus, smoking habit, and lipoprotein(a) >50 mg/dL were independently associated to ASCVD. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02693548.

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.

Proteomic analysis of plasma from patients during an acute coronary syndrome.

OBJECTIVES: The aim of this study was to analyze modifications in the plasma protein map during an acute coronary syndrome (ACS) using proteomics. BACKGROUND: Proteomics is a new technology that allows the detection and identification of several proteins at a given time in a sample. METHODS: Plasma from 19 patients, 11 with acute myocardial infarction (AMI) and 8 with unstable angina (UA), was investigated. The control group included nine age-matched volunteers. RESULTS: In two-dimensional electrophoresis using a pH range of 4 to 7, constant differences were found in at least four different areas within the plasma protein map. In area 1, we identified the presence of seven alpha(1)-antitrypsin (AAT) isoforms in plasma from control subjects. alpha(1)-antitrypsin isoform 1 was undetectable in plasma from UA and AMI patients. The AAT isoforms 5, 6, and 7 were reduced in plasma from AMI patients when compared with UA patients. Three fibrinogen gamma chain isoforms were identified in area 2. Fibrinogen gamma chain isoforms 1 and 2 were increased in AMI patients with respect to UA patients. Five apolipoprotein A-I isoforms were identified in area 3. All of them were reduced in plasma from AMI patients with respect to UA patients. In area 4, the gamma-immunoglobulin heavy chains were detected and were found increased in plasma from ACS patients. CONCLUSIONS: Plasma proteomic analysis makes it possible to develop a map of the protein isoforms that are expressed in plasma during an ACS.

[Effect of HMG-CoA reductase inhibition on endothelial dysfunction-inducing protein in hypercholesterolemic rabbits]. / Efecto de la inhibición de la HMG-CoA reductasa sobre la proteína inductora de disfuncion endotelial en conejos hipercolesterolémicos.

INTRODUCTION AND OBJECTIVES: In our laboratory, we recently obtained evidence that cultured bovine endothelial cells contain cytosolic proteins that form complexes with the 3'-unstranslated region of endothelial nitric oxide synthase (eNOS) mRNA and are associated with its destabilization. The aim of this study was to determine the presence of such proteins and the level of eNOS expression in hypercholesterolemic rabbits as an in vivo model of endothelial dysfunction. METHODS AND RESULTS: Endothelium-dependent relaxation in response to acetylcholine was reduced in aortic segments from hypercholesterolemic rabbits compared with controls. Treatment of hypercholesterolemic rabbits with simvastatin (25 mg/kg body weight/day) restored endothelium-dependent relaxation. Aortic eNOS expression was reduced in hypercholesterolemic rabbits and was accompanied by enhanced binding activity of a 60-KDa cytosolic protein and reduced stability of eNOS mRNA. Simvastatin treatment upregulated eNOS expression and reduced the interaction of cytosolic protein with the 3'-untranslated region of eNOS mRNA. CONCLUSIONS: These results demonstrate the presence of a 60-KDa protein that binds to eNOS mRNA and reduces eNOS expression in the vascular wall.

Reduction of the soluble cyclic GMP vasorelaxing system in the vascular wall of stroke-prone spontaneously hypertensive rats: effect of the alpha1 -receptor blocker doxazosin.

OBJECTIVE: The aim of the present study was to analyse the nitric oxide (NO)/cyclic GMP (cGMP) relaxing system in spontaneously hypertensive rats of the stroke-prone substrain (SHRSP). DESIGN: The study was performed in 20-week-old SHRSP rats. A group of normotensive Wistar-Kyoto (WKY) rats was used as control. RESULTS: The endothelium-dependent relaxation to acetylcholine was reduced in SHRSP rats (n = 15). No modifications in the expression of the endothelial nitric oxide synthase were found in the vascular wall of WKY rats (n = 15) and SHRSP rats. SHRSP rats demonstrated an impaired relaxing response to the NO-donor sodium nitroprusside that was accompanied by a reduction in the level of the main second messenger of NO, cyclic GMP. The expression of the soluble guanylate cyclase (sGC) beta1-subunit was markedly reduced in the vascular wall of SHRSP rats. In the experimental model of SHRSP, an increased concentration of catecholamines has been reported. Therefore, we evaluated the effect of an alpha1-receptor blocker, doxazosin, on the NO/cGMP system. Doxazosin [10 mg/kg body weight (bw) per day for 15 days, n = 15] reduced mean arterial pressure (MAP) in SHRSP rats. Treatment with doxazosin preserved the endothelium-independent relaxation response to sodium nitroprusside in aortic segments from SHRSP rats which was associated with an increased expression of the sGC beta1-subunit. A dose of doxazosin (1 mg/kg bw per day, n = 15) that did not modify MAP partially prevented sGC protein expression in the vascular wall. CONCLUSIONS: Independently of the endothelial NO-generating system, impaired vasorelaxation could also result from vascular smooth muscle cell layer dysfunction. Doxazosin treatment improved the endothelial-independent relaxation and preserved the cGMP generating system in the vascular wall of SHRSP rats.

Nitric oxide production by neutrophils obtained from patients during acute coronary syndromes: expression of the nitric oxide synthase isoforms.

OBJECTIVES: To analyze the differences in the nitric oxide (NO) forming system between neutrophils obtained from patients during unstable angina (UA) and during acute myocardial infarction (AMI). BACKGROUND: Neutrophils are involved in the regulation of thrombus formation through the release of active substances such as NO. Acute myocardial infarction is the result of an occlusive thrombus; unstable angina is attributed to intermittent thrombus formation. METHODS: We studied 49 patients admitted to hospital within 24 h after the onset of chest pain: 31 experienced AMI and 18 experienced UA. Acute myocardial infarction was defined as CK greater than two-fold the upper limit of normal value of biochemical laboratory, with CK-MB >10% total CK. Unstable angina was defined as transient ST segment changes without significant increases in CK and CK-MB. RESULTS: The amount of NO generated by neutrophils from AMI patients was significantly higher than that generated by neutrophils from UA patients. Neutrophils from UA and AMI patients showed low levels of endothelial-like NO synthase protein expression and a marked expression of the inducible NO synthase (iNOS) isoform. Although neutrophils from patients during acute coronary syndromes generated high amounts of NO, they did not demonstrate an increased ability to stimulate cyclic guanosine monophosphate (cGMP) synthesis in platelets. This lack of activity to release NO by neutrophils from patients during AMI was unrelated to a defect in the platelet cGMP-forming system; sodium nitroprusside, an exogenous NO donor, similarly increased cGMP levels in platelets from AMI patients and healthy donors. CONCLUSIONS: Neutrophils from patients during AMI and UA showed an increased production of NO and a marked expression of the iNOS isoform. However, NO released from these neutrophils showed a deficient functionality. These findings could have clinical implications because they show differences in thrombus growth in patients with UA versus patients with AMI.