Background
The aim of this study is to confirm the diagnostic performance of the Chylomicron to very low‐density lipoproteins triglycerides (CM/VLDL‐TG) ratio, the triglycerides to cholesterol ratio ...(TG/TC) and a dichotomic rule including the tryglycerides to apolipoprotein B (TG/APOB) ratio for the presence of Type I hyperlipoproteinemia (HPLI) in patients with severe hypertriglyceridemia (sHTG) that were at high risk for familial chylomicronemia syndrome (FCS).
Methods
Two cohorts (derivation and validation) of patients with sHTG were included in the study. Anthropometric, clinical, biochemical and genetic data were obtained. The CM/VLDL‐TG, TG/TC and TG/APOB ratios were calculated. Finally, a diagnostic performance study was developed to establish sensitivity, specificity and cut‐offs by a ROC curve analysis in the derivation cohort as well as agreement and predictive values in the validation cohort.
Results
Patients with FCS in both cohorts showed an earlier presence in pancreatitis, greater number of acute pancreatitis episodes and lower BMI. FCS patients also showed higher ratios of CM/VLDL‐TG, TG/TC and TG/APOB ratios, whereas their HDL‐C, LDL‐C and APOB levels were lower than in non‐FCS patients. Sensitivity and agreement were low for both the TG/TC and TG/APOB ratios, although predictive values were good. The CM/VLDL‐TG ratio showed greatest sensitivity, specificity, agreement and predictive values for cut‐off of 3.8 and 4.5.
Conclusions
Our results suggest that in subjects at high risk of FCS a total serum TG/TC ratio or TG/APOB ratio are feasible to initially screen for HLPI; however, a CM/VLDL‐TG ratio ≥4.5 is a better diagnostic criterion for HPLI.
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
Atherosclerosis is a chronic inflammatory disease caused by the accumulation of cholesterol in the intima. Proprotein convertase subtilisin/kexin type 9 inhibitors (iPCSK9) can reduce low-density ...lipoprotein (LDL) cholesterol levels by 60%, but there is still no evidence that they can lower markers of systemic inflammation such as high-sensitivity C-reactive protein (hsCRP). Acute-phase serum glycoproteins are upregulated in the liver during systemic inflammation, and their role as inflammatory biomarkers is under clinical evaluation. In this observational study, we evaluate the effects of iPCSK9 on glycoproteins (Glyc) A, B and F. Thirty-nine patients eligible for iPCSK9 therapy were enrolled. One sample before and after one to six months of iPCSK9 therapy with alirocumab was obtained from each patient. Lipids, apolipoproteins, hsCRP and PCSK9 levels were measured by biochemical analyses, and the lipoprotein and glycoprotein profiles were measured by 1H nuclear magnetic resonance (1H-NMR). The PCSK9 inhibitor reduced total (36.27%,
< 0.001), LDL (55.05%,
< 0.001) and non-high-density lipoprotein (HDL) (45.11%,
< 0.001) cholesterol, apolipoprotein (apo) C-III (10%,
< 0.001), triglycerides (9.92%,
< 0.001) and glycoprotein signals GlycA (11.97%,
< 0.001), GlycB (3.83%,
= 0.017) and GlycF (7.26%,
< 0.001). It also increased apoA-I (2.05%,
= 0.043) and HDL cholesterol levels (11.58%,
< 0.001). Circulating PCSK9 levels increased six-fold (626.28%,
< 0.001). The decrease in Glyc signals positively correlated with the decrease in triglycerides and apoC-III. In conclusion, in addition to LDL cholesterol, iPCSK9 therapy also induces a reduction in systemic inflammation measured by 1H-NMR glycoprotein signals, which correlates with a decrease in triglycerides and apoC-III.
Purpose of Review
Familial hypercholesterolemia is a high cardiovascular risk disorder. We will review the role of lipoprotein(a) in cardiovascular risk and in aortic valve stenosis in familial ...hypercholesterolemia, as well as its association with their phenotype, and strategies to identify this high-risk population.
Recent Findings
Patients with familial hypercholesterolemia have higher lipoprotein(a) levels mainly due to an increased frequency of LPA variants, and the cardiovascular risk is increased twofolds when both conditions coexist. Also, an increased risk for aortic valve stenosis and valve replacement has been observed with high lipoprotein(a) levels. Assessment of lipoprotein(a) during the cascade screening for familial hypercholesterolemia is a good opportunity to identify this high-risk population.
Summary
High cardiovascular risk in familial hypercholesterolemia is increased even more when lipoprotein(a) is also elevated. Measurement of lipoprotein(a) in these patients is crucial to identify those subjects who need to intensify LDL-cholesterol reduction pending availability of lipoprotein(a)-specific treatments.
Familial hypercholesterolemia (FH) is a frequent disorder associated with premature atherosclerotic cardiovascular disease. Different clinical diagnosis criteria are available, and cost of genetic ...testing has been reduced in the last years; however, most cases are not diagnosed worldwide. Patients with FH are at high cardiovascular risk and the risk can be reduced with lifelong lifestyle and pharmacological treatment. Statins and ezetimibe are available as generic drugs in most countries reducing the cost of treatment. However, the use of high-intensity statins combined with ezetimibe and PCSK9 inhibitors, if necessary, is low for different reasons that contribute to a high number of patients not reaching LDL-C targets according to guidelines. On the other hand, cardiovascular risk varies greatly in families with FH; therefore, risk stratification strategies including cardiovascular imaging is another element to consider for improving care and management of FH. There are numerous barriers depending on the awareness, knowledge, perception of risk, management and care of patients living with FH that impact in the diagnosis and treatment of the disorder. In this contemporary review, we analyze different barriers in the diagnosis and care of patients to improve patients' care and prevention of atherosclerotic cardiovascular disease and describe recent advances and strategies to improve the gaps in the care of FH, including global collaboration and advocacy.
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.
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.
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).
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.
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•Coronary atherosclerosis burden may be quantified and plaque characteristics analysed in the coronary artery tree using coronary CTA in patients with familial hypercholesterolemia (FH).•Coronary atherosclerosis, beyond coronary calcium, is highly prevalent in asymptomatic patients with FH.•By means of coronary CTA, we can study every component of the coronary atherosclerotic plaque.•Plaque burden, calcified plaque burden and non-calcified plaque burden are independently related to the cardiovascular risk and cardiovascular prognosis.•This new diagnostic approach might improve the risk re-stratification and management optimization, allowing more personalized lipid lowering treatment, such us the use of PCSK9 inhibitors.
Cerebrovascular Disease and Statins Beltrán Romero, Luis M; Vallejo-Vaz, Antonio J; Muñiz Grijalvo, Ovidio
Frontiers in cardiovascular medicine,
12/2021, Letnik:
8
Journal Article
Recenzirano
Odprti dostop
Elevated low-density lipoprotein-cholesterol (LDL-C) is a causal factor for the development of atherosclerotic cardiovascular disease (ASCVD); accordingly, LDL-C lowering is associated with a ...decreased risk of progression of atherosclerotic plaques and development of complications. Currently, statins play a central role in any ASCVD management and prevention strategies, in relation to their lipid-lowering action and potentially to pleiotropic effects. After coronary artery disease, stroke is the most frequent cause of ASCVD mortality and the leading cause of acquired disability, a major public health problem. There is often a tendency to aggregate all types of stroke (atherothrombotic, cardioembolic, and haemorrhagic), which have, however, different causes and pathophysiology, what may lead to bias when interpreting the results of the studies. Survivors of a first atherothrombotic ischemic stroke are at high risk for coronary events, recurrent stroke, and vascular death. Although epidemiological studies show a weak relationship between cholesterol levels and cerebrovascular disease as a whole compared with other ASCVD types, statin intervention studies have demonstrated a decrease in the risk of stroke in patients with atherosclerosis of other territories and a decrease in all cardiovascular events in patients who have had a stroke. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial demonstrated the benefit of high doses of atorvastatin in the secondary prevention of ischemic stroke. In this review, we discuss the evidence, use and recommendations of statins in the primary and secondary prevention of stroke, and their role in other scenarios such as the acute phase of ischemic stroke, cerebral hemorrhage, cardioembolic stroke, small vessel disease, and cognitive impairment.
Familial Hypercholesterolemia (FH) is characterized by elevated LDL-cholesterol (LDL-C) and high atherosclerosis risk. The impact of different dietary patterns on atherosclerosis biomarkers has been ...poorly studied in FH.
This study verified the association of adherence to a Mediterranean diet with biomarkers of dyslipidemia and low-grade inflammation in molecularly proven FH adults from Brazil (BR) and Spain (SP).
In this cross-sectional study adherence to the Mediterranean diet was assessed by a validated score and generalized estimating equations were used to evaluate its association with plasma LDL-C, apolipoprotein-B (ApoB) and high sensitivity C-reactive protein (hs-CRP) concentrations. We included 92 (mean age 45 years, 58.7% females) and 98 FH individuals (mean age 46.8 years, 60.2% females) respectively from BR and SP. FH causing variants did not differ between countries. LDL-C, ApoB and hs-CRP concentrations were higher in BR than in SP: 179 (135–250) and 161 (133–193) mg/dL; 141 (109–181) and 103 (88–134) mg/dL; and 1.6 (0.8–4.0) and 0.8 (0.4–1.5) mg/L respectively (all p < 0.001). Most of BR had low adherence (n = 77, 83.7%), while the majority of SP were divided into moderate (n = 35, 35.7%) and strong adherence to the Mediterranean diet (n = 37, 37.8%), p < 0.001. There was a significant inverse association of adherence to the Mediterranean diet score with higher LDL-C, ApoB, and hs-CRP after adjusting for socio economic parameters, caloric and fatty acid intakes as well as pharmacological lipid lowering therapies.
Higher adherence to a Mediterranean diet was associated with better dyslipidemia and low-grade inflammation profiles in FH.
•The impact of different dietary patterns on atherosclerosis biomarkers has been poorly studied in FH.•Dyslipidemia and inflammation were higher in Brazilian FH patients.•Spanish FH patients had greater adherence to a Mediterranean diet.•Adherence to a Mediterranean diet was associated with less dyslipidemia and inflammation.•Diet may influence cardiovascular risk in FH.
Abstract
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.
Graphical Abstract
Graphical Abstract
Persistence with long-term PCSK9 inhibitors treatment and its effectiveness in familial hypercholesterolaemia.
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