Homeostasis Model Assessment for Insulin Resistance Mediates the Positive Association of Triglycerides with Diabetes.

Elevated circulating triglyceride levels have been linked to an increased risk of diabetes, although the precise mechanisms remain unclear. This study aimed to investigate whether low-density lipoprotein (LDL) cholesterol, homeostatic model assessment (HOMA) for insulin resistance, and C-reactive protein (CRP) served as mediators in this association across a sample of 18,435 US adults. Mediation analysis was conducted using the PROCESS Version 4.3 Macro for SPSS. Simple mediation analysis revealed that all three potential mediators played a role in mediating the association. However, in parallel mediation analysis, where all three mediators were simultaneously included, HOMA for insulin resistance remained a significant mediator (indirect effect coefficient, 0.47; 95% confidence interval [CI], 0.43-0.52; p < 0.05) after adjusting for all tested confounding factors. Conversely, LDL cholesterol (indirect effect coefficient, -0.13; 95% CI, -0.31-0.05; p > 0.05) and C-reactive protein (indirect effect coefficient, 0.01; 95% CI, -0.003-0.02; p > 0.05) ceased to be significant mediators. HOMA for insulin resistance accounted for 49% of the association between triglycerides and diabetes. In conclusion, HOMA for insulin resistance was the dominant mediator underlying the association between triglycerides and diabetes. Therefore, reducing triglyceride levels may hold promise for improving insulin sensitivity in diabetic patients.

Cardiovascular risk in myositis patients compared with the general population.

OBJECTIVES: We aimed to evaluate cardiovascular (CV) risk in patients with idiopathic inflammatory myopathies (IIM) compared with healthy controls (HC) and to assess its association with disease-specific features. METHODS: Ninety IIM patients and 180 age-/sex-matched HC were included. Subjects with a history of CV disease (angina pectoris, myocardial infarction and cerebrovascular/peripheral arterial vascular events) were excluded. All participants were prospectively recruited and underwent examinations of carotid intima-media thickness (CIMT), pulse wave velocity (PWV), ankle-brachial index (ABI), and body composition. The risk of fatal CV events was evaluated by the Systematic COronary Risk Evaluation (SCORE) and its modifications. RESULTS: Compared with HC, IIM patients had a significantly higher prevalence of traditional CV risk factors, carotid artery disease (CARD), abnormal ABI and PWV. After propensity score matching (using traditional CV risk factors), the prevalence of CARD and pathological PWV remained significantly higher in IIM than HC. No significant difference in SCORE was observed. The most unfavourable CV risk profile was observed in patients with necrotizing myopathy, especially in statin-induced anti-HMGCR+ patients. The calculated CV risk scores by SCORE, SCORE2 and SCORE multiplied by the coefficient 1.5 (mSCORE) were reclassified according to CIMT and the presence of carotid plaques. SCORE was demonstrated to be most inaccurate in predicting CV risk in IIM. Age, disease activity, lipid profile, body composition parameters and blood pressure were the most significant predictors of CV risk in IIM patients. CONCLUSION: Significantly higher prevalence of traditional risk factors and subclinical atherosclerosis was observed in IIM patients compared with HC.

Genetic risk score in patients with the APOE2/E2 genotype as a predictor of familial dysbetalipoproteinemia.

BACKGROUND: Familial dysbetalipoproteinemia (FD) is an autosomal recessive (rarely dominant) inherited disorder that is almost exclusively associated with the apolipoprotein E gene (APOE) variability. Nonetheless, only a small proportion of APOE2/E2 subjects develop the phenotype for mixed dyslipidemia; the context of other trigger metabolic or genetic factors remains unknown. METHODS: One hundred and one patients with FD and eighty controls (all APOE2/E2 homozygotes; rs429358) were screened for 18 single-nucleotide polymorphisms (SNPs) within the genes involved in triglyceride metabolism. RESULTS: Two SNPs were significantly associated with the FD phenotype (rs439401 within APOE; P < 0.0005 and rs964184 within ZPR1/APOA5/A4/C3/A1 gene cluster; P < 0.0001). Unweighted genetic risk scores - from these two SNPs (GRS2), and, also, additional 13 SNPs with P-value below 0.9 (GRS15) - were created as an additional tool to improve the risk estimation of FD development in subjects with the APOE2/E2 genotype. Both GRS2 and GRS15 were significantly (P < 0.0001) increased in patients and both GRSs discriminated almost identically between the groups (P = 0.86). Subjects with an unweighted GRS2 of three or more had an almost four-fold higher risk of FD development than other individuals (OR 3.58, CI: 1.78-7.18, P < 0.0005). CONCLUSIONS: We identified several SNPs that are individual additive factors influencing FD development. The use of unweighted GRS2 is a simple and clinically relevant tool that further improves the prediction of FD in APOE2/E2 homozygotes with corresponding biochemical characteristics.

Lipid-lowering in diabetes: An update.

Atherosclerotic cardiovascular disease (ASCVD) is accelerated in people with diabetes. Dyslipidemia, hyperglycemia, oxidative stress, and inflammation play a role via a variety of mechanisms operative in the artery wall. In addition, some unique features predispose people with type 1 diabetes to accelerated atherosclerosis. Various organizations have created guidelines that provide advice regarding screening, risk assessment, and roadmaps for treatment to prevent ASCVD in diabetes. Management of dyslipidemia, especially with statins, has proven to be of immense benefit in the prevention of clinical CVD. However, since many patients fail to attain the low levels of low-density lipoproteins (LDL) recommended in these guidelines, supplemental therapy, such as the addition of ezetimibe, bempedoic acid or PCSK9 inhibitors, is often required to reach LDL goals. As a result, the upfront use of combination therapies, particularly a statin plus ezetimibe, is a rational initial approach. The addition to statins of drugs that specifically lower triglyceride levels has not proven beneficial, although the addition of icosapent-ethyl has been shown to be of value, likely by mechanisms independent of triglyceride lowering. Newer treatments in development, including apoC-III and ANGPTL3 inhibitors, seem promising in further reducing apoB-containing lipoproteins.

Reporting LDL cholesterol results by clinical biochemistry laboratories in Czechia and Slovakia to improve the detection rate of familial hypercholesterolemia.

Introduction: This survey aims to assess the implementation of recommendations from the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) by clinical biochemistry laboratories in Czechia and Slovakia in their policies for reporting low-density lipoprotein cholesterol (LDL-C) concentrations. Materials and methods: The web-based survey was distributed to all 383 Czech and Slovak clinical biochemistry laboratories that measure lipids by external quality assessment provider SEKK. A total of 17 single-answer questions were included. The questionnaire was focused on the detection and decision points in familial hypercholesterolemia (FH). All survey answers were taken into account. The laboratories followed the EFLM and EAS guidelines when they reported an interpretative comment considering FH diagnosis in adults. Results: A total of 203 (53%) laboratories answered. Only 5% of laboratories added interpretative comments considering FH diagnosis when LDL-C concentrations are above 5.0 mmol/L in adults, and 3% of laboratories added interpretative comments considering FH diagnosis when LDL-C concentrations are above 4.0 mmol/L in children. Only 7% of laboratories reported goals for all cardiovascular risk categories (low, moderate, high, very high). Non-HDL cholesterol concentrations were calculated by 74% of responders. A significant number (51%) of participants did not measure apolipoprotein B, and 59% of laboratories did not measure lipoprotein(a). Conclusions: Only a small portion of laboratories from Czechia and Slovakia reported high LDL-C results with interpretative comments considering FH diagnosis in adults, the laboratories did not follow the guidelines.

Regional differences in physicians' behavior and factors influencing the intensity of PCSK9 inhibitor therapy with alirocumab: a subanalysis of the ODYSSEY APPRISE study.

Background: Despite better accessibility of the effective lipid-lowering therapies, only about 20% of patients at very high cardiovascular risk achieve the low-density lipoprotein cholesterol (LDL-C) goals. There is a large disparity between European countries with worse results observed for the Central and Eastern Europe (CEE) patients. One of the main reasons for this ineffectiveness is therapeutic inertia related to the limited access to appropriate therapy and suitable dosage intensity. Thus, we aimed to compare the differences in physicians' therapeutic decisions on alirocumab dose selection, and factors affecting these in CEE countries vs. other countries included in the ODYSSEY APPRISE study. Methods: ODYSSEY APPRISE was a prospective, single-arm, phase 3b open-label (≥12 weeks to ≤30 months) study with alirocumab. Patients received 75 or 150 mg of alirocumab every 2 weeks, with dose adjustment during the study based on physician's judgment. The CEE group in the study included Czechia, Greece, Hungary, Poland, Romania, Slovakia, and Slovenia, which we compared with the other nine European countries (Austria, Belgium, Denmark, Finland, France, Germany, Italy, Spain, and Switzerland) plus Canada. Results: A total of 921 patients on alirocumab were involved [modified intention-to-treat (mITT) analysis], including 114 (12.4%) subjects from CEE countries. Therapy in CEE vs. other countries was numerically more frequently started with lower alirocumab dose (75 mg) at the first visit (74.6 vs. 68%, p = 0.16). Since week 36, the higher dose was predominantly used in CEE patients (150 mg dose in 51.6% patients), which was maintained by the end of the study. Altogether, alirocumab dose was significantly more often increased by CEE physicians (54.1 vs. 39.9%, p = 0.013). Therefore, more patients achieved LDL-C goal at the end of the study (<55 mg/dl/1.4 mmol/L and 50% reduction of LDL-C: 32.5% vs. 28.8%). The only factor significantly influencing the decision on dose of alirocumab was LDL-C level for both countries' groups (CEE: 199.2 vs. 175.3 mg/dl; p = 0.019; other: 205.9 vs. 171.6 mg/dl; p < 0.001, for 150 and 75 mg of alirocumab, respectively) which was also confirmed in multivariable analysis (OR = 1.10; 95% CI: 1.07-1.13). Conclusions: Despite larger unmet needs and regional disparities in LDL-C targets achievement in CEE countries, more physicians in this region tend to use the higher dose of alirocumab, they are more prone to increase the dose, which is associated with a higher proportion of patients reaching LDL-C goals. The only factor that significantly influences decision whether to increase or decrease the dose of alirocumab is LDL-C level.

The way to data: opinions and recommendations for the provision of health data for secondary use.

Healthcare data held by state-run organisations is a valuable intangible asset for society. Its use should be a priority for its administrators and the state. A completely paternalistic approach by administrators and the state is undesirable, however much it aims to protect the privacy rights of persons registered in databases. In line with European policies and the global trend, these measures should not outweigh the social benefit that arises from the analysis of these data if the technical possibilities exist to sufficiently protect the privacy rights of individuals. Czech society is having an intense discussion on the topic, but according to the authors, it is insufficiently based on facts and lacks clearly articulated opinions of the expert public. The aim of this article is to fill these gaps. Data anonymization techniques provide a solution to protect individuals' privacy rights while preserving the scientific value of the data. The risk of identifying individuals in anonymised data sets is scalable and can be minimised depending on the type and content of the data and its use by the specific applicant. Finding the optimal form and scope of deidentified data requires competence and knowledge on the part of both the applicant and the administrator. It is in the interest of the applicant, the administrator, as well as the protected persons in the databases that both parties show willingness and have the ability and expertise to communicate during the application and its processing.

Low LDL-C goal attainment in patients at very high cardiovascular risk due to lacking observance of the guidelines on dyslipidaemias.

Dyslipidemias are defined as a wide range of abnormalities of the lipid profile. Treatment guidelines recommend aiming at lowering LDL-C. We investigated the adherence of Czech cardiologists to the dyslipidaemia treatment guidelines, especially in the management of patients with high and very high cardiovascular risk. In this retrospective cross-sectional multicentric study data from medical records of 450 adults with ASCVD, enrolled between June 2021 and January 2022, were analysed. Demographics, clinical outcomes, medical history, LLT treatment and other medications were collected. The physicians were to include patients at a very high risk of ASCVD and to complete a general questionnaire on their personal therapeutic preferences. Objectively assessed, only 80% of total patients (N = 450) enrolled in the study were at very high risk of ASCVD, and 12.7% of patients were at high risk of ASCVD, respectively. In total, 55 (13.1%) patients were diagnosed with familial hypercholesterolemia, and 39.1% of them had a positive family history of ASCVD. Generally, only 20.5% of patients reached the 2019 LDL-C goals- 19.4% of very high risk patients and 28.1% of high risk patients, respectively. 61% of the physicians preferred a slow and careful up-titration of the dose, which is contradictory to the guidelines. Only 17% of the physicians increased the statin dose or added/combined/changed the treatment to achieve the LDL-C goals as soon as possible. Surprisingly, in up to 61.5% of patients at very high risk who did not meet the LDL-C goals, their physicians stated subjective satisfaction with the treatment and considered no change needed. Among very high and high risk patients receiving lipid-lowering therapy, with high treatment adherence, the LDL-C goal attainment is very low and LLT utilization is rather sub-optimal. Improving observance of the guidelines by physicians bears a substantial potential for LDL-C goal attainment and thus improving overall benefit for patients for no additional costs.

Inclisiran, Low-Density Lipoprotein Cholesterol and Lipoprotein (a).

Dyslipidemia treatment is of major importance in reducing the risk of atherosclerotic cardiovascular disease (ASCVD), which is still the most common cause of death worldwide. During the last decade, a novel lipid-lowering drug category has emerged, i.e., proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Apart from the two available anti-PCSK9 monoclonal antibodies (alirocumab and evolocumab), other nucleic acid-based therapies that inhibit or "silence" the expression of PCSK9 are being developed. Among them, inclisiran is the first-in-class small interfering RNA (siRNA) against PCSK9 that has been approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of hypercholesterolemia. Importantly, inclisiran therapy may improve low-density lipoprotein cholesterol (LDL-C) target achievement by offering a prolonged and significant LDL-C-lowering effect with the administration of only two doses per year. The present narrative review discusses the ORION/VICTORION clinical trial program that has been designed to investigate the impact of inclisiran on atherogenic lipoproteins and major adverse cardiac events in different patient populations. The results of the completed clinical trials are presented, focusing on the effects of inclisiran on LDL-C and lipoprotein (a) (Lp(a)) levels as well as on other lipid parameters such as apolipoprotein B and non-high-density lipoprotein cholesterol (non-HDL-C). Ongoing clinical trials with inclisiran are also discussed.

Bempedoic acid in the management of lipid disorders and cardiovascular risk. 2023 position paper of the International Lipid Expert Panel (ILEP).

Cardiovascular disease (CVD) is a chronic non-communicable disease (NCD) and the predominant cause of morbidity and mortality worldwide. Substantial reductions in the CVD prevalence have been achieved in recent years by the attenuation of risk factors (particularly hypertension and dyslipidaemias) in primary and secondary prevention. Despite the remarkable success of lipid lowering treatments, and of statins in particular, in reducing the risk of CVD, there is still an unmet clinical need for the attainment of guideline lipid-targets in even 2/3 of patients. Bempedoic acid, the first in-class inhibitor of ATP-citrate lyase presents a new approach to lipid-lowering therapy. By reducing the endogenous production of cholesterol, upstream of the rate-limiting enzyme HMG-CoA-reductase, i.e., the target of statins, bempedoic acid reduces circulating plasma concentrations of low-density lipoprotein cholesterol (LDL-C), and major adverse CVD events (MACE). Bempedoic acid has the potential to contribute to the reduction of CVD risk not only as monotherapy, but even further as part of a lipid-lowering combination therapy with ezetimibe, reducing LDL-C cholesterol up to 40%. This position paper of the International Lipid Expert Panel (ILEP) summarises the recent evidence around the efficacy and safety of bempedoic acid and presents practical recommendations for its use, which complement the 'lower-is-better-for-longer' approach to lipid management, which is applied across international guidelines for the management of CVD risk. Practical evidence-based guidance is provided relating to the use of bempedoic acid in atherosclerotic CVD, familial hypercholesterolaemia, and statin intolerance. Although there are still no sufficient data avilable for the role of bempedoic acid in the primary prevention of CVD, its favourable effects on plasma glucose and inflammatory markers makes this drug a rational choice in the patient-centred care of specific groups of primary prevention.

Implications of ACC/AHA Versus ESC/EAS LDL-C Recommendations for Residual Risk Reduction in ASCVD: A Simulation Study From DA VINCI.

PURPOSE: Low-density lipoprotein cholesterol (LDL-C) recommendations differ between the 2018 American College of Cardiology/American Heart Association (ACC/AHA) and 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for patients with atherosclerotic cardiovascular disease (ASCVD) (< 70 vs. < 55 mg/dl, respectively). In the DA VINCI study, residual cardiovascular risk was predicted in ASCVD patients. The extent to which relative and absolute risk might be lowered by achieving ACC/AHA versus ESC/EAS LDL-C recommended approaches was simulated. METHODS: DA VINCI was a cross-sectional observational study of patients prescribed lipid-lowering therapy (LLT) across 18 European countries. Ten-year cardiovascular risk (CVR) was predicted among ASCVD patients receiving stabilized LLT. For patients with LDL-C ≥ 70 mg/dl, the absolute LDL-C reduction required to achieve an LDL-C of < 70 or < 55 mg/dl (LDL-C of 69 or 54 mg/dl, respectively) was calculated. Relative and absolute risk reductions (RRRs and ARRs) were simulated. RESULTS: Of the 2039 patients, 61% did not achieve LDL-C < 70 mg/dl. For patients with LDL-C ≥ 70 mg/dl, median (interquartile range) baseline LDL-C and 10-year CVR were 93 (81-115) mg/dl and 32% (25-43%), respectively. Median LDL-C reductions of 24 (12-46) and 39 (27-91) mg/dl were needed to achieve an LDL-C of 69 and 54 mg/dl, respectively. Attaining ACC/AHA or ESC/EAS goals resulted in simulated RRRs of 14% (7-25%) and 22% (15-32%), respectively, and ARRs of 4% (2-7%) and 6% (4-9%), respectively. CONCLUSION: In ASCVD patients, achieving ESC/EAS LDL-C goals could result in a 2% additional ARR over 10 years versus the ACC/AHA approach.

A Phase 3 Randomized Controlled Trial to Evaluate Efficacy and Safety of New-Formulation Zenon (Rosuvastatin/Ezetimibe Fixed-Dose Combination) in Primary Hypercholesterolemia Inadequately Controlled by Statins.

OBJECTIVE: In primary hypercholesterolemia many people treated with statins do not reach their plasma LDL-C goals and are at increased risk of cardiovascular disease (CVD). This study aimed to evaluate efficacy and safety of a new fixed-dose combination (FDC) formulation of rosuvastatin/ezetimibe (R/E) in this population. METHODS: This was a multicenter, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-arm study of FDC R/E in people with primary hypercholesterolemia at very high risk (VHR) or high risk (HR) of CVD, inadequately controlled with 20 mg or 10 mg stable daily dose of rosuvastatin or equipotent dose of another statin. The primary objective was to demonstrate superiority of FDC R/E versus rosuvastatin monotherapy uptitrated to 40 mg (R40) or 20 mg (R20) in reduction of LDL-C after 6 weeks. RESULTS: Randomized VHR participants (n = 244) were treated with R40, R40/E10, or R20/E10; randomized HR participants (n = 208) received R10/E10 or R20. In VHR participants, superiority of R40/E10 and R20/E10 versus R40 was demonstrated on LDL-C percent change from baseline to Week 6 with least squares mean differences (LSMD) of -19.66% (95% CI: -29.48% to -9.84%; P < .001) and -12.28% (95% CI: -22.12% to -2.44%; P = .015), respectively. In HR participants, superiority of R10/E10 over R20 was not demonstrated (LSMD -5.20%; 95% CI: -15.18% to 4.78%; P = .306), despite clinically relevant LDL-C reduction with R10/E10. No unexpected safety findings were reported. CONCLUSIONS: The results from this study suggest that R/E FDCs improve LDL-C reduction and goal achievement in people with primary hypercholesterolemia inadequately controlled with statins and at VHR/HR of CVD.

The time is now: Achieving FH paediatric screening across Europe - The Prague Declaration.

Familial hypercholesterolaemia (FH) is the most common inherited metabolic disorder characterized by high cholesterol and if left untreated leads to premature cardiovascular disease, such as heart attacks. Treatment that begins early in life, particularly in childhood, is highly efficacious in preventing cardiovascular disease and cost-effective, thus early detection of FH is crucial. However, in Europe, less than 10% of people living with FH are diagnosed and even less receive life-saving treatment. The Prague Declaration is a call to action for national and European Union policymakers and decision-makers and a result of the Czech EU Presidency meeting on FH Paediatric Screening (early detection of inherited high cholesterol) at the Czech Senate in Prague on 6th September 2022. It builds on a considerable body of evidence which was discussed at the Technical Meeting under the auspices of the Slovenian EU Presidency in October 2021. The Prague meeting addressed the outstanding barriers to the systematic implementation of FH paediatric screening across Europe. In this article, we present the key points from the Prague meeting and concrete actions needed to move forward.

Cardiovascular Risk in Myositis Patients Compared to the General Population: Preliminary Data From a Single-Center Cross-Sectional Study.

Background: Idiopathic inflammatory myopathies (IIM) are associated with systemic inflammation, limited mobility, and glucocorticoid therapy, all of which can lead to metabolism disturbances, atherogenesis, and increased cardiovascular (CV) risk. The aim of this study was to assess the CV risk in IIM patients and healthy controls (HC), and its association with disease-specific features. Methods: Thirty nine patients with IIM (32 females; mean age 56; mean disease duration 4.8 years; dermatomyositis: n = 16, polymyositis: n = 7, immune-mediated necrotizing myopathy: n = 8, anti-synthetase syndrome: n = 8) and 39 age-/sex-matched HC (32 females, mean age 56) without rheumatic diseases were included. In both groups, subjects with a history of CV disease (angina pectoris, myocardial infarction, cerebrovascular, and peripheral arterial vascular events) were excluded. Muscle involvement, disease activity, and tissue damage were evaluated (Manual Muscle Test-8, Myositis Intention to Treat Activity Index, Myositis Damage Index). Comorbidities and current treatment were recorded. All participants underwent examinations of carotid intima-media thickness (CIMT), pulse wave velocity (PWV), ankle-brachial index (ABI), and body composition (by densitometry and bioelectric impedance). The risk of fatal CV events was evaluated by the Systematic COronary Risk Evaluation (SCORE, charts for the European population) and its modifications. Results: Compared to HC, there was no significant difference in IIM patients regarding blood pressure, ABI, PWV, CIMT, and the risk of fatal CV events by SCORE or SCORE2, or subclinical atherosclerosis (CIMT, carotid plaques, ABI, and PWV). The calculated CV risk scores by SCORE, SCORE2, and SCORE multiplied by the coefficient 1.5 (mSCORE) were reclassified according to the results of carotid plaque presence and CIMT; however, none of them was demonstrated to be significantly more accurate. Other significant predictors of CV risk in IIM patients included age, disease duration and activity, systemic inflammation, lipid profile, lean body mass, and blood pressure. Conclusions: No significant differences in CV risk factors between our IIM patients and HC were observed. However, in IIM, CV risk was associated with age, disease duration, duration of glucocorticoid therapy, lipid profile, and body composition. None of the currently available scoring tools (SCORE, SCORE2, mSCORE) used in this study seems more accurate in estimating CV risk in IIM.

The role of cholesterol metabolism in multiple sclerosis: From molecular pathophysiology to radiological and clinical disease activity.

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS leading to demyelination and axonal degeneration. An increasing body of evidence suggests that lipid metabolism is associated with adverse clinical and MRI outcomes in MS. In this review we summarize the findings of association between low-density lipoproteins (LDL), high-density lipoproteins (HDL), their apolipoproteins and oxysterols with clinical and radiological disease activity in MS. Although the causality between disease activity in MS and abnormalities in lipid metabolism has not yet been elucidated, we suggest that advances in this field of research have the potential to improve understanding of MS pathophysiology and the identification of new treatment targets and strategies.

Familial Hypercholesterolemia: Real-World Data of 1236 Patients Attending a Czech Lipid Clinic. A Retrospective Analysis of Experience in More than 50 years. Part II. Clinical Characteristics.

Introduction: Patients with familial hypercholesterolemia (FH) are at increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Aim of study: To perform a retrospective analysis of data to assess the effects of individual lipoproteins and other risk factors (RFs) on the development of ASCVD and to compare these parameters in individuals with versus without ASCVD. Patients and methods: Our study group included a total of 1,236 patients with FH (395 men and 841 women with a mean age of 44.8 ± 16.7 years) attending a single lipid clinic. The diagnosis of FH was established using the Dutch Lipid Clinic Network score (DLCN). Among the 1236 FH patients, 1,008 of them [854 suspected with LDL receptor-mediated FH and 154 with familial defective apolipoprotein B-100 (FDB)] were genetically analysed. Their RFs were assessed based on the patients' clinical characteristics. Results: While patients with ASCVD had higher baseline LDL-C, TC, TG and Lp(a) compared with patients without this diagnosis, this ratio was just the opposite by the follow-up. The highest statistically significant differences were seen in the baseline levels of Lp(a) and, quite surprisingly, TG. Except for Lp(a), the levels of all lipid parameters declined significantly over time. While the incidence of diabetes and arterial hypertension was not higher in our group compared with the general population, these patients were at a more significant risk of ASCVD. Conclusion: Familial hypercholesterolemia is a major RF for the development of ASCVD. While our analysis confirmed the important role of LDL-C, it also corroborated a strong correlation between ASCVD and other lipid parameters, and Lp(a) and TG in particular. Familial hypercholesterolemia is not the only RF and, to reduce cardiovascular risk of their patients, physicians have to search for other potential RFs. Patients diagnosed to have FH benefit from attending a specialized lipid clinic perse.

Familial Hypercholesterolemia: Real-World Data of 1236 Patients Attending a Czech Lipid Clinic. A Retrospective Analysis of Experience in More than 50 years. Part I: Genetics and Biochemical Parameters.

Introduction: The cause of familial hypercholesterolemia (FH) is defect in LDL receptor or familial defect of apolipoprotein B-100 (FDB) or, rarely, defect in proprotein convertase subtilisin/kexin type 9. Identification and treatment of patients with FH improves their prognosis. Our data represent retrospective analysis of 50 years of specialised care in our center. Patients and Methods: A group of 1236 FH patients (841 women, 395 men; 993 study subjects and 243 relatives; mean age 44.8 ± 16.7 years) included 154 FDB patients followed at the Lipid Clinic of the General University Hospital in Prague since the mid-1960s to the present. Clinical diagnosis was based on the Dutch Lipid Clinic Network Criteria. Genetic analysis was performed using PCR-RFLP to detect FDB and apolipoprotein E (APOE) polymorphism. Biochemical data were collected and statistically analysed. Results: At baseline, mean LDL-C and total cholesterol (TC) levels of all FH patients combined were 6.49 ± 1.92 mmol/L and 8.95 ± 1.95 mmol/L, respectively. Their LDL-C levels decreased to 3.26 ± 1.57 mmol/L and TC levels to 5.43 ± 1.69 mmol/L during follow-up. In the subgroup of LDL receptor-mediated FH (non-FDB) patients, baseline LDL-C and TC levels of 6.61 ± 1.95 mmol/L and 9.09 ± 1.97 mmol/L declined to 3.21 ± 1.60 mmol/L and 5.39 ± 1.72 mmol/L, respectively, during follow-up. In the FDB subgroup of patients, baseline levels of LDL-C and TC were 5.57 ± 1.46 mmol/L and 7.88 ± 1.58 mmol/L decreasing to 3.45 ± 0.24 mmol/L and 5.58 ± 1.37 mmol/L, respectively, during follow-up. Differences were also found in the effects of various APOE isoforms on lipid lowering. A significant decrease in lipid parameters was observed with the E2E2 isoform whereas a minimal decrease was seen with the E4E4 and E3E3 isoforms. Conclusion: Whereas, overall, non-FDB patients had higher baseline lipid levels, these levels declined more appreciably compared with FDB patients during follow-up. Our retrospective analysis also found different effects of APOE isoforms on the decrease in lipid levels.

Beta-blockers for Atherosclerosis Prevention: a Missed Opportunity?

PURPOSE OF REVIEW: Current guidelines for the management of arterial hypertension endorse ß-adrenergic receptor blocking agents (beta-blockers, BBs) as being particularly useful for hypertension in specific situations such as symptomatic angina, tachycardia, post-myocardial infarction, heart failure with reduced ejection fraction (HFrEF), and as an alternative to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in hypertensive women planning pregnancy or at least of child-bearing potential. One of the most common uses of BBs is in patients with a recent myocardial infarction, with or without hypertension. Although this one use is specifically in a setting of atherosclerotic cardiovascular disease (ASCVD), it is not primarily for atheroprevention, but rather for cases with impaired systolic function, and it is intended primarily to lessen adverse cardiac remodeling and worsening of congestive heart failure (CHF). The BB class consists of numerous agents which differ widely in pharmacologic properties and physiologic effects. These differences include selectivity for ß-adrenergic receptors and their subtypes, hydro- or lipophilicity, effects on blood pressure and heart rate, influence on lipoprotein and glucose metabolism, and direct impact on the artery wall, including platelet reactivity, endothelial function, infiltration of inflammatory cells and on inflammation per se, and on smooth muscle cell proliferation. Importantly, BBs are not commonly used for prevention of atherosclerosis or ASCVD per se. Many studies of early-generation BBs showed adverse effects on lipoprotein levels and metabolism of glucose and insulin and thus discouraged their use in atheroprevention. Nevertheless, newer BBs often have neutral or favorable metabolic effects on these important factors in ASCVD pathophysiology, and recent scientific studies now document direct beneficial effects of BBs on the artery wall. This document reviews both types of newer data, not only to encourage consideration of BB treatment to reduce ASCVD in the present, but also to call for future research to better explore the clinical settings in which BBs may be proven to have additional benefit in preventing ASCVD when added to the better-established treatments for dyslipidemia and diabetes. RECENT FINDINGS: Relatively recent publications have clarified the diversity among BBs regarding adverse, neutral, or favorable effects on lipoproteins (especially triglycerides (TG) and low-density lipoprotein (LDL)) and on glucose/insulin metabolism. Specifically, the newer BBs (metoprolol ER, carvedilol ER, bisoprolol, and nebivolol) are now documented to be metabolically beneficial. These new data are complex but instructive regarding potential mechanisms of the diverse effects of various BBs on metabolism. Further and more importantly, these new data refute the traditional, but now outmoded, concept that BBs are universally harmful metabolically and therefore must be used sparingly, if at all, for atheroprevention. Recent studies have also reported exciting new data regarding how certain BBs can reduce platelet adhesion and improve the function of the major cell types in the artery wall, including the endothelium, macrophages, and smooth muscle cells. Specifically, BBs can improve endothelial function by enhancing arterial vasodilation and by reducing monocyte adhesion and transmigration. Further, BBs can decrease numbers and activity of inflammatory cells, including decreasing proliferation of smooth muscle cells and their transformation into inflammatory cells. These data help with the crucial step of distinguishing among available BBs regarding their likely overall arterial effects, whether to accelerate or prevent the development of atherosclerosis. In this regard, there is even some limited published information beyond these intermediary steps, going directly to the clinically more important endpoints of atherosclerosis and ASCVD events. The negative metabolic effects observed with the use of traditional/earlier generations of BBs have discouraged use of any BBs to prevent ASCVD. These adverse effects are not seen, however, with newer BBs. Thus, BBs continue to be a useful component of combination regimens not only in the treatment of arterial hypertension, heart failure, and arrhythmia, but also potentially in the prevention of atherosclerosis and ASCVD. Despite this exciting potential, further research is greatly needed to better establish the possible benefits of the most promising BBs as they might work in combination with other better-established atheropreventive agents. Specifically, there is a need for randomized, prospective, cardiovascular outcome trials (CVOTs) in high-risk patients, adding a BB to background LDL-lowering (statins, etc.), TG-lowering (specifically icosapent ethyl, which reduces ASCVD in patients with high TG, although apparently not via TG-lowering), and/or anti-diabetic (sodium glucose transport-2 inhibitors, SGLT2i, and glucagon-like protein-1 receptor agonists, GLP1-RA) treatments, as indicated in a given subject population.