High Lipoprotein(a) May Explain One-Quarter of Clinical Familial Hypercholesterolemia Diagnoses in Danish Lipid Clinics.

CONTEXT: Cholesterol carried in lipoprotein(a) adds to measured low-density lipoprotein cholesterol (LDL-C) and may therefore drive some diagnoses of clinical familial hypercholesterolemia (FH). OBJECTIVE: We investigated plasma lipoprotein(a) in individuals referred to Danish lipid clinics and evaluated the effect of plasma lipoprotein(a) on a diagnosis of FH. METHODS: Individuals referred to 15 Danish lipid clinics who were suspected of having FH according to nationwide referral criteria were recruited between September 1, 2020 and November 30, 2021. All individuals were classified according to the Dutch Lipid Clinical Network criteria for FH before and after LDL-C was adjusted for 30% cholesterol content in lipoprotein(a). We calculated the fraction of individuals fulfilling a clinical diagnosis of FH partly due to elevated lipoprotein(a). RESULTS: We included a total of 1166 individuals for analysis, of whom 206 fulfilled a clinical diagnosis of FH. Median lipoprotein(a) was 15 mg/dL (29 nmol/L) in those referred and 28% had lipoprotein(a) greater than or equal to 50 mg/dL (105 nmol/L), while 2% had levels greater than or equal to 180 mg/dL (389 nmol/L). We found that in 27% (55/206) of those fulfilling a clinical diagnosis of FH, this was partly due to high lipoprotein(a). CONCLUSION: Elevated lipoprotein(a) was common in individuals referred to Danish lipid clinics and in one-quarter of individuals who fulfilled a clinical diagnosis of FH, this was partly due to elevated lipoprotein(a). These findings support the notion that the LPA gene should be considered an important causative gene in patients with clinical FH and further support the importance of measuring lipoprotein(a) when diagnosing FH as well as for stratification of cardiovascular risk.

Genetic testing increases the likelihood of a diagnosis of familial hypercholesterolaemia among people referred to lipid clinics: Danish national study.

BACKGROUND AND AIMS: It is unclear to what extent genetic testing improves the ability to diagnose familial hypercholesterolaemia (FH). We investigated the percentage with FH among individuals referred to Danish lipid clinics, and evaluated the impact of genetic testing for a diagnosis of FH. METHODS: From September 2020 through November 2021, all patients referred for possible FH to one of the 15 Danish lipid clinics were invited for study participation and >97% (n = 1488) accepted. The Dutch Lipid Clinical Network criteria were used to diagnose clinical FH. The decision of genetic testing for FH was based on local practice. RESULTS: A total of 1243 individuals were referred, of whom 25.9% were diagnosed with genetic and/or clinical FH. In individuals genetically tested (n = 705), 21.7% had probable or definite clinical FH before testing, a percentage that increased to 36.9% after genetic testing. In individuals with unlikely and possible FH before genetic testing, 24.4% and 19.0%, respectively, had a causative pathogenic variant. CONCLUSIONS: In a Danish nationwide study, genetic testing increased a diagnosis of FH from 22% to 37% in patients referred with hypercholesterolaemia suspected of having FH. Importantly, approximately 20% with unlikely or possible FH, who without genetic testing would not have been considered having FH (and family screening would not have been undertaken), had a pathogenic FH variant. We therefore recommend a more widespread use of genetic testing for evaluation of a possible FH diagnosis and potential cascade screening.

Equivalent Impact of Elevated Lipoprotein(a) and Familial Hypercholesterolemia in Patients With Atherosclerotic Cardiovascular Disease.

BACKGROUND: Genetically elevated plasma lipoprotein(a) and familial hypercholesterolemia each result in premature atherosclerotic cardiovascular disease (ASCVD); however, a direct comparison in the same population is needed of these 2 genetic traits on the risk of ASCVD. OBJECTIVES: We determined the level of plasma lipoprotein(a) that is equivalent to low-density lipoprotein (LDL) cholesterol in clinically and genetically diagnosed familial hypercholesterolemia on risk of myocardial infarction and ASCVD. METHODS: We examined the CGPS (Copenhagen General Population Study) with determination of lipoprotein(a) and familial hypercholesterolemia in 69,644 individuals followed for 42 years, during which time, 4,166 developed myocardial infarction and 11,464, ASCVD. RESULTS: For risk of myocardial infarction, the plasma lipoprotein(a) level equivalent to LDL cholesterol in clinical familial hypercholesterolemia was 67 mg/dL (142 nmol/L) for MEDPED (Make Early Diagnosis to Prevent Early Death), 110 mg/dL (236 nmol/L) for Simon Broome, 256 mg/dL (554 nmol/L) for possible DLCN (Dutch Lipid Clinic Network), and 402 mg/dL (873 nmol/L) for probable+definite DLCN, whereas it was 180 mg/dL (389 nmol/L) for genetic familial hypercholesterolemia. Corresponding values for ASCVD were 130 mg/dL (280 nmol/L), 150 mg/dL (323 nmol/L), 227 mg/dL (491 nmol/L), 391 mg/dL (849 nmol/L), and 175 mg/dL (378 nmol/L), respectively. Individuals with both elevated lipoprotein(a) and either familial hypercholesterolemia or a family history of premature myocardial infarction had a higher risk of myocardial infarction and ASCVD compared with individuals with only 1 of these genetic traits, with the highest HRs being for lipoprotein(a) upper 20% vs lower 50% of 14.0 (95% CI: 9.15-21.3) for myocardial infarction and 5.05 (95% CI: 3.41-7.48) for ASCVD. CONCLUSIONS: Lipoprotein(a) levels equivalent to LDL cholesterol in clinical and genetic familial hypercholesterolemia were 67 to 402 mg/dL and 180 mg/dL, respectively, for myocardial infarction and 130 to 391 mg/dL and 175 mg/dL, respectively, for ASCVD.

Genetic testing is essential for initiating statin therapy in children with familial hypercholesterolemia: Examples from Scandinavia.

BACKGROUND AND AIMS: In familial hypercholesterolemia (FH), statin treatment should be considered from 8 to 10 years of age, but the prevalence of statin use among children is not known. METHODS: Statin use (2008-2018) among children aged 10-14 and 15-19 years was obtained from the national prescription databases in Norway, Sweden and Denmark. We assumed that all statin users in these age groups had FH, and that the estimated prevalence of FH is 1 in 250 inhabitants. Changes in prevalence rates of statin use between 2008 and 2018 by country, age and sex were estimated using the Joinpoint Regression Program version 4.8.0.1. Differences in prevalence rate ratio each year between countries were analyzed using Poisson regression. RESULTS: Among children aged 10-14 years, there was a significant increase in statin use in Norway and Denmark between 2008 and 2018, while in Sweden an increase was only seen after 2014. Among children aged 15-19 years, an increase in statin use was only observed in Norway and Sweden between 2008 and 2018. Statin use was significantly more prevalent in Norway than in Sweden and Denmark each year, and in 2018 the proportion of children using statins was 4-5 times (10-14 years) and 3 times (15-19 years) higher in Norway compared with Sweden and Denmark. In 2018 in Norway, 19% and 35% of children aged 10-14 years and 15-19 years estimated to have FH used statins respectively; corresponding percentages in Sweden were 4.5% and 10%, and in Denmark 3% and 12%. In Norway, the increase in statin use between 2008 and 2018 roughly corresponded to the increase in children with genetically verified FH. CONCLUSIONS: Between 2008 and 2018, statin use increased in children aged 10-19 years in Norway, Sweden and Denmark, but with large differences between the countries; statin use was 3-5 times more prevalent in Norway than in Sweden and Denmark, which may be due to a more widespread use of genetic testing for FH in Norway.

Autosomal recessive hypercholesterolemia in a kindred of Syrian ancestry.

Autosomal recessive hypercholesterolemia is a rare genetic disorder due to homozygosity or compound heterozygosity for mutations in the low-density lipoprotein receptor adapter protein 1 gene (LDLRAP1), resulting in elevated low-density lipoprotein cholesterol (LDL-C) levels, large xanthomas, and increased cardiovascular risk. Here, we describe a Danish family of Syrian ancestry carrying a frameshift mutation in LDLRAP1, previously only described in Sardinia and Sicily in Italy and in Spain. In 2 children homozygous for this mutation, we evaluate the effect of long-term lipid-lowering treatment with atorvastatin as monotherapy or in combination with ezetimibe. At referral to the lipid clinic at Viborg Regional Hospital, 3 of 4 children had LDL-C levels of 468, 538, and 371 mg/dL, respectively, with 1 child already showing cutaneous xanthomas at 10 years of age. For comparison, the fourth child and the parents had LDL-C levels of 85, 116, and 124 mg/dL. Genetic testing revealed that all 3 children with severely elevated LDL-C were homozygous for a rare frameshift mutation in LDLRAP1, p.His144GlnfsTer27 (c.431dupA), whereas the fourth child and both parents were heterozygous for this mutation. Lipid-lowering treatment was started in the 2 oldest children (at 10 and 7 years of age). Atorvastatin (40 mg/d) combined with ezetimibe (10 mg/d) reduced LDL-C by 75% in the first child and resulted in near-complete regression of xanthomas. In the second child, atorvastatin (40 mg/d) as monotherapy reduced LDL-C by 61%. Both regimens were superior to treatment with pravastatin as monotherapy (20 mg/d) and to pravastatin in combination with cholestyramine (2 g twice daily). High-intensity statin therapy alone or in combination with ezetimibe resulted in marked reductions in LDL-C in 2 children homozygous for a rare frameshift mutation in LDLRAP1 and lead to regression of large xanthomas.

Prevalence of clinical familial hypercholesterolaemia among patients with high cholesterol levels.

INTRODUCTION: Familial hypercholesterolaemia (FH) can be diagnosed using clinical criteria or by direct mutation identification. The prevalence of clinical FH in Danish lipid clinics remains unknown. The objective of this study was to explore the prevalence of clinical FH in patients admitted on suspicion of FH with plasma low-density lipoprotein cholesterol (LDL-C) concentration ≥ 5.0 mmol/l. METHODS: We reviewed the medical records of 653 patients consecutively (from 1 January 2013 to 1 May 2017) referred to the lipid clinic at Viborg Regional Hospital, Denmark. Patients with LDL-C concentration > 4.9 mmol/l were selected. Clinical FH was assessed using the Dutch Lipid Clinic Network (DLCN) and Simon Broome criteria. RESULTS: Using DLCN, 315 patients (median 82% (95% confidence interval (CI): 78-86%)) had possible FH, 33 patients (median 9% (95% CI: 6-11%)) had probable FH and 36 patients (median 9% (95% CI: 6-12%)) had definite FH. Thus, a total of 69 patients (median 18% (95% CI: 14-22%)) had probable/definite FH. Using the Simon Broome criteria, 284 (median 74% (95% CI: 70-78%)) patients did not have FH, 67 patients (median 17% (95% CI: 14-21%)) had possible FH and 33 patients (median 9% (95% CI; 6-11%)) had definite FH, resulting in a total of 100 (median 26% (95% CI: 22-30%)) patients having possible/definite FH. The concordance between DLCN and Simon Broome FH was high among patients with definite FH (> 90%), but low among patients with probable or possible FH. CONCLUSIONS: Clinical FH was common among patients with LDL-C concentration ≥ 5.0 mmol/l referred to a Danish lipid clinic. However, the concordance between the DLCN and the Simon Broome criteria was low in a specialised clinical setting. FUNDING: The study was supported by a SANOFI grant. TRIAL REGISTRATION: not relevant.

A population-based screening study for cardiovascular diseases and diabetes in Danish postmenopausal women: acceptability and prevalence.

BACKGROUND: Reducing women's cardiovascular risk and the economic costs associated with cardiovascular diseases (CVD) and diabetes (DM) continues to be a challenge. Whether a multifaceted CVD screening programme is beneficial as a preventive strategy in women remains uncertain. The aim of this study was to investigate the prevalence of CVD and DM as well as the acceptability toward screening and preventive actions. METHODS: An observational study was performed among all women born in 1936, 1941, 1946 and 1951 living in Viborg Municipality, Denmark, from October 2011. In total, 1984 were invited to screening for abdominal aortic aneurysm (AAA), peripheral arterial disease (PAD), carotid plaque (CP), hypertension (HT), atrial fibrillation (AF), DM and dyslipidaemia. Participants with positive tests were offered prophylactic intervention including follow-up consultations in case of AAA, PAD and/or CP. Participants with AAA ≥ 50 mm were referred to specialists in vascular surgery. Women with AF or potential familial hypercholesterolaemia (FH) were referred to cardiology work-up. RESULTS: Among those invited, 1474 (74.3%) attended screening, but the attendees' share decreased with increasing age groups (p < 0.001). AAA was diagnosed in 10 (0.7%) women, PAD in 101 (6.9%) and CP in 602 (40.8%). The percentage of women with these conditions rose with increasing age group (p < 0.05). Unconfirmed potential HT was observed in 94 (6.4%), unknown AF in 6 (0.4%), DM in 14 (1%) and potential FH in 35 (2.4%). None of these findings differed across age groups. Among the 631 women diagnosed with AAA, PAD and/or CP, 182 (28.8%) were already in antiplatelet and 223 (35.3%) in lipid-lowering therapy prior to screening. Antiplatelet therapy was initiated in 215 (34.1%) and lipid-lowering therapy in 191 (30.3%) women. Initiation of antiplatelet and lipid-lowering therapy was further recommended to 134 (21.2%) and 141 (22.4%) women, respectively, who hesitated to follow the recommendation. CONCLUSIONS: The study recorded an acceptable total attendance rate, even though a significantly lower attendance rate was observed in the eldest women. The identified hesitation towards prophylactic therapy may affect the rationale and effectiveness of CVD screening, and hesitation seems a critical issue that should be addressed in the design of future screening programmes.

Familial hypercholesterolemia among unselected contemporary patients presenting with first myocardial infarction: Prevalence, risk factor burden, and impact on age at presentation.

BACKGROUND: Familial hypercholesterolemia (FH) is a hereditary disease carrying a substantial lifetime risk of coronary heart disease. OBJECTIVE: To assess the prevalence of FH and its impact on age at presentation among unselected patients with first myocardial infarction (MI). METHODS: In a multi-center cross sectional study, we identified 1381 unselected patients presenting with a first MI between 2010 and 2012. Clinical FH was assessed using both the Dutch Lipid Clinic Network (DLCN) criteria and the Simon Broome criteria. RESULTS: Based on the DLCN criteria, 2.0% of patients with first MI had "probable/definite" FH, whereas 4.7% had "possible" FH according to the Simon Broome criteria. In the 291 (21%) patients with premature MI, 6.9% had "probable/definite" FH (DLCN criteria), and 11.0% had "possible" FH (Simon Broome criteria). Nearly all premature "probable/definite" and "possible" FH patients had at least one additional marker of high cardiovascular risk including current smoking (72%-80%) and hypertension (40%-44%). In multivariable-adjusted linear regression modeling, patients with "probable/definite" FH using DLCN criteria had their first MI 14.6 years (95% confidence interval [CI], 9.6-19.6 years) earlier than non-FH patients. Likewise, "possible" FH patients using Simon Broome criteria were associated with having an MI 9.1 years (95% CI = 6.3-12.4) earlier than non-FH patients. CONCLUSION: Clinical FH is common and associated with markedly earlier age of first MI, especially when combined with additional markers of high risk, indicating an unmet need for earlier identification of FH to ensure global risk factor control. First MI constitutes a unique opportunity to detect families with unknown FH.

Routine transradial coronary angiography in unselected patients.

OBJECTIVES: To measure and compare the results of changing from routine transfemoral to routine transradial coronary angiography performed by a single operator. DESIGN: A learning period of 3 months for the transradial procedure with 43 selected patients was followed by a 12-month routine period with 243 unselected patients. The success and complication rates, contrast volumes, catheter and X-ray times were measured and compared to results of a preceding period where the transfemoral approach was used. Follow-up was performed in the transradial groups 1.5-25 months after the procedure. RESULTS: Of the non-selected patients, 9% were deemed unsuitable for the radial procedure. In the remaining 91% in which the transradial route was attempted, success was achieved in 91%. The complication rate was 2.7%. Increased operator experience reduces catheter and fluoroscopy times. At follow-up, 4.7% of the radial arteries were occluded, but the patients were without clinical sequelae. The occlusion rate was significantly higher with an unsuccessful procedure. CONCLUSIONS: Transradial coronary angiography can be performed safely and with acceptable image quality in non-selected patients after a learning period of 43 cases. Total procedure time is shorter than with the transfemoral approach. There were no bleeding complications and no procedure-related complications that required treatment.

Reduced consumption of analgesics in patients with diabetes mellitus admitted to hospital for acute myocardial infarction.

In a case-control study, the consumption of analgesics was analysed in 39 patients with diabetes, admitted with acute myocardial infarction (MI). The control group comprised of non-diabetics with MI was computer-matched to the diabetic group with respect to age and sex as well as enzyme-estimated size of the infarction. The median number of injections of opioid analgesics in the diabetes and non-diabetes groups was 2 and 5, respectively (0.01 less than P less than 0.05), and the median consumption of morphine was 20 mg and 35 mg, respectively (0.01 less than P less than 0.05). There was no statistically significant trend for the duration of pain to be shorter in the diabetes group. There was no difference between the two groups with respect to number of patients with Q-wave infarct, initial heart rate-blood pressure product or body weight, all of which are possible confounders. We conclude that diabetics admitted with acute myocardial infarction have a lower consumption of analgesics than non-diabetics.