Familial hypercholesterolemia is a frequent genetic disease associated with lifelong elevation of LDL-cholesterol and premature atherosclerotic cardiovascular disease (ASCVD). Statins are the ...cornerstone of treatment. However, with the introduction of novel LDL-cholesterol-lowering therapies, it is necessary to identify familial hypercholesterolemia patients presenting a significantly high residual ASCVD risk. The aim of this review is to provide an update on the recent literature concerning cardiovascular risk stratification including the role of coronary imaging.
Several factors have shown to be independent predictors of ASCVD in familial hypercholesterolemia. These include clinical scores with cardiovascular risk factors, coronary imaging and novel protein biomarkers. However, the recent introduction of the SAFEHEART risk-equation (SAFEHEART-RE) could allow a more accurate ASCVD risk prediction in familial hypercholesterolemia.
This article highlights the SAFEHEART-RE as a model to predict incident ASCVD in familial hypercholesterolemia. This equation is a simple and widely applicable tool for use in every clinical setting. Furthermore, coronary atherosclerosis assessed by coronary computed-tomographic angiography (coronary-CTA) is independently associated to the cardiovascular risk estimated according to the SAFEHEART-RE. This equation, as well as coronary-CTA and new biomarkers, could increase individual ASCVD risk stratification and could improve the efficiency and the use of new lipid-lowering therapies in familial hypercholesterolemia.
Familial hypercholesterolemia (FH) and elevated lipoprotein(a) Lp(a) are inherited disorders associated with premature atherosclerotic cardiovascular disease (ASCVD). Cascade testing is recommended ...for FH, but there are no similar recommendations for elevated Lp(a).
This study investigated whether testing for Lp(a) was effective in detecting and risk stratifying individuals participating in an FH cascade screening program.
Family members (N = 2,927) from 755 index cases enrolled in SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) were tested for genetic FH and elevated Lp(a) via an established screening program. Elevated Lp(a) was defined as levels ≥50 mg/dl. The authors compared the prevalence and yield of new cases of high Lp(a) in relatives of FH probands both with and without high Lp(a), and prospectively investigated the association between elevated Lp(a) and ASCVD events among family members.
Systematic screening from index cases with both FH and elevated Lp(a) identified 1 new case of elevated Lp(a) for every 2.4 screened. Opportunistic screening from index cases with FH, but without elevated Lp(a), identified 1 individual for 5.8 screened. Over 5 years’ follow-up, FH (hazard ratio HR: 2.47; p = 0.036) and elevated Lp(a) (HR: 3.17; p = 0.024) alone were associated with a significantly increased risk of experiencing an ASCVD event or death compared with individuals with neither disorder; the greatest risk was observed in relatives with both FH and elevated Lp(a) (HR: 4.40; p < 0.001), independent of conventional risk factors.
Testing for elevated Lp(a) during cascade screening for FH is effective in identifying relatives with high Lp(a) and heightened risk of ASCVD, particularly when the proband has both FH and elevated Lp(a).
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—URLhttps://www.clinicaltrials.gov. Unique identifierNCT02693548.
Dyslipidemia and aortic valve disease Mata, Pedro; Alonso, Rodrigo; Pérez de Isla, Leopoldo ...
Current opinion in lipidology,
12/2021, Letnik:
32, Številka:
6
Journal Article
Recenzirano
Purpose of review
Degenerative aortic stenosis (AS) is one of the most prevalent heart valve diseases in the adult population. The understanding of AS pathophysiology and involved risk factors have ...recently undergone a great advance, with low-density lipoprotein cholesterol (LDL-C), lipoprotein (a) Lp(a) and other clinical conditions taking on a relevant role. Although little is known about the prevention of AS, we can progressively find more evidence of the possible use of drugs to control risk factors as tools that may delay the progression to severe AS and aortic valve replacement.
Recent findings
Several factors have shown to be solid predictors of the development of AS. Mendelian randomization and observational studies on risk factors specifically lipid factors, such as hypercholesterolemia, Lp(a), proprotein convertase subtilisin/kexin type 9 and hypertension have provided meaningful new information. The SAFEHEART study has significantly contributed to define the role of LDL-C and Lp(a) in AS.
Summary
In this review we discuss the interrelationship of dyslipidemia, especially hypercholesterolemia and Lp(a) in the development and prognosis of valvular AS. New imaging tools may contribute to its early detection. Future studies with proprotein convertase subtilisin/kexin type 9 inhibitors and specific therapies to lower Lp(a) might contribute to delay AS development.
Is it Time for Single-Pill Combinations in Dyslipidemia? Schiele, François; Pérez de Isla, Leopoldo; Arca, Marcello ...
American journal of cardiovascular drugs : drugs, devices, and other interventions,
05/2022, Letnik:
22, Številka:
3
Journal Article
Odprti dostop
Despite the availability of lipid-lowering therapies (LLTs) that are safe and effective, the overall rate of low-density lipoprotein cholesterol (LDL-C) control at a population level in real-life ...studies is low. Higher-intensity treatment, earlier intervention, and longer-term treatment have all been shown to improve outcomes. However, in clinical practice, actual exposure to LLT is a product of the duration and intensity of, and adherence to, the treatment. To increase exposure to LLTs, the European Society of Cardiology guidelines recommended a stepwise optimization of LLTs by increasing statin intensity to the maximally tolerated dose, with subsequent addition of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Evidence from randomized controlled trials performed in a range of patients suggested that adding ezetimibe to statins rather than doubling the statin dose resulted in significantly more patients at LDL-C goal and significantly fewer patients discontinuing treatment because of adverse events. In addition, data showed that combination treatments effectively increased exposure to LLT. Despite these data and recommendations, optimization of LLT is often limited to increasing statin dose. Therapeutic inertia and poor treatment adherence are significant and prevalent barriers to increasing treatment exposure. They are known to be influenced by pill burden and complexity of treatment. Single-pill combinations provide a strategic approach that supports the intensification of treatment without increasing pill burden or treatment complexity. Single-pill combinations, compared with free associations, have been shown to increase the adherence to LLT and the percentage of patients at LDL-C goal.
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:URLhttp://clinicaltrials.gov. Unique identifierNCT02693548.
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.
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.
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 (
<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 (
<0.001). A significant change in the characteristics of the coronary atherosclerosis was also found: an increase in the proportion of calcified (+0.3%;
<0.001) and mainly fibrous (+6.2%;
<0.001) plaque, accompanied by a decrease in the percentage of fibro-fatty (-3.9%;
<0.001) and necrotic plaque (-0.6%;
<0.001).
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.
URL: https://www.
gov; Unique identifier: NCT05465278.
Abstract
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.
Graphical abstract
Obesity is considered as a strong risk factor for cardiovascular morbidity and mortality. 3D‐wall motion tracking echocardiography (3D‐WMT) provides information regarding different parameters of left ...ventricular (LV) myocardial deformation. Our aim was to assess the presence of early myocardial deformation abnormalities in nonselected obese children free from other cardiovascular risk factors. Thirty consecutive nonselected obese children and 42 healthy volunteer children were enrolled. None of them had any cardiovascular risk factor. Every subject underwent a 2D‐echo examination and a 3D‐WMT study. Mean age was 13.9 ± 2.56 and 13.25 ± 2.68 years in the nonobese and obese groups, respectively (59.7% and 40.3% male). Statistically significant differences were found for: interventricular septum thickness, LV posterior wall thickness, LV end‐diastolic volume, LV end‐systolic volume, left atrium volume, LV mass, and lateral annulus peak velocity. Regarding the results obtained by 3D‐WMT assessment, all the evaluated parameters were statistically significantly different between the two groups. When the influence of obesity on the different echocardiographic variables was evaluated by means of multivariate logistic regression analysis, the strongest relationship with obesity was found for LV average circumferential strain (β‐coefficient: 0.74; r2: 0.55; P: 0.003). Thus, obesity cardiomyopathy is associated not only with structural cardiac changes, but also with myocardial deformation changes. Furthermore, this association occurs as early as in the childhood and it is independent from any other cardiovascular risk factor. The most related parameter to obesity is LV circumferential strain.
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