IntroductionFamilial hypercholesterolaemia (FH) is the most common monogenic autosomal dominant genetic disorder and is associated with a high risk of premature atherosclerotic cardiovascular ...disease. The prevalence of FH has been reported to be particularly high in certain founder populations. The population of the Faroe Islands is a founder population, but the prevalence of FH has never been investigated here. We aim to assess the prevalence of FH and to describe the genetic and clinical characteristics and potential causes of FH in the Faroe Islands. Furthermore, we aim to investigate whether indicators of subclinical coronary artery disease are associated with FH.Methods and analysisThe prevalence of FH will be estimated based on an electronic nationwide laboratory database that includes all measurements of plasma lipid levels in the Faroe Islands since 2006. Subsequently, we will identify and invite subjects aged between 18 and 75 years registered with a plasma low-density lipoprotein cholesterol above 6.7 mmol/L for diagnostic evaluation. Eligible FH cases will be matched to controls on age and sex. We aim to include 120 FH cases and 120 controls.Detailed information will be collected using questionnaires and interviews, and a physical examination will be undertaken. An adipose tissue biopsy and blood samples for genetic testing, detailed lipid analyses and samples for storage in a biobank for future research will be collected. Furthermore, FH cases and controls will be invited to have a transthoracic echocardiography and a cardiac CT performed.Ethics and disseminationThe project has been approved by the Ethical Committee and the Data Protection Agency of the Faroe Islands. The project is expected to provide important information, which will be published in international peer-reviewed journals.
Tissue levels of n-3 polyunsaturated fatty acids (PUFAs) have been inversely related with risk of myocardial infarction (MI). Whether ratios of n-3 to n-6 PUFAs, reflecting both dietary intake of n-3 ...PUFAs and competing n-6 PUFAs, are better predictors of future MI than n-3 PUFA fractions is unclear. We aimed at investigating whether such ratios in adipose tissue better predict MI than n-3 PUFA fractions.
Subcutaneous adipose tissue biopsies were obtained in a random sample (n = 3,500) of the Diet, Cancer and Health cohort (n = 57,053). Adipose tissue content of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), arachidonic acid (AA) and linoleic acid was determined using gas chromatography. Fractions of selected n-3 PUFAs and n-3/n-6 PUFA ratios were correlated to the 15-year occurrence of MI in a case-cohort design.
A total of 2,406 participants experienced an MI during follow-up. Adipose tissue total marine n-3 PUFAs, EPA+DHA, EPA, EPA/AA, DHA/AA and (EPA + DPA + DHA)/AA were all inversely associated with risk of incident MI. Evaluating the predictive power (Harrel's C-index) of the selected metrics, fractions of marine n-3 PUFAs and ratios of EPA/AA, DHA/AA, (EPA + DHA)/AA and (EPA + DPA + DHA)/AA all refined risk prediction over age and sex alone. At multivariable analyses, however, the above ratios were the only metrics providing additional risk prediction. Differences in ratios were related to differences in food intake.
Both adipose tissue n-3 PUFAs fractions and ratios of n-3 PUFAs/AA were associated with a lower occurrence of MI, but ratios provided superior risk prediction. Dietary strategies affecting n-3/n-6 PUFA ratios should be further investigated for prediction of MI with dietary interventions at the population level and in intervention studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Familial hypercholesterolemia (FH) is one of the most common hereditary disorders. The population of the Faroe Islands was established by few founders, and genetic drift may have influenced lipid ...levels. The aim of this study was to describe the lipid distribution by providing age and sex-specific lipid values and to investigate the prevalence of FH in the Faroe Islands.
We used an electronic nationwide laboratory database that included lipid measurements obtained in the Faroe Islands between January 2006 and September 2020. Percentiles of lipid levels were calculated using quantile regression. The prevalence of FH was estimated according to the Make Early Diagnosis Prevent Early Death (MEDPED) diagnostic criteria and according to the LDL-C cut-off levels included in the Dutch Lipid Clinic Network (DLCN) criteria using generalized linear models with robust variance.
According to the MEDPED age-specific cut-offs for LDL-C, a total of 216 subjects met the criteria for definite FH among 30,711 individuals corresponding to a prevalence of 0.70% (1:142). According to the LDL-C cut-offs included in the DLCN criteria, a total of 3,823 (1:8) subjects could be classified as having possible FH, and 10 (1:3,071) subjects could be classified as probable FH corresponding to a prevalence of 12.4% and 0.03%, respectively. Also, we found significant differences in lipid levels according to sex and age groups.
The Faroe Islands might represent a founder population with a prevalence of possible FH as high as 1 in 8. Further investigation of genetic and clinical characteristics of FH in the Faroe Islands is needed.
•Very high prevalence of possible familial hypercholesterolemia in the Faroe Islands.•Higher prevalence of familial hypercholesterolemia in women compared to men.•Significant differences in lipid levels according to sex and age groups.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ischemic stroke is a major cause of death and morbidity worldwide. It has been suggested that polyunsaturated fatty acids (PUFAs) may be associated with a lower risk ischemic stroke, but this has ...been far less studied than their role for coronary heart disease. In this paper, we summarize the main findings from previous follow-up studies investigating associations between intake or biomarkers of the major PUFAs including alpha-linolenic acid (ALA), marine n-3 PUFAs and linoleic acid (LA) and the development of ischemic stroke. Several follow-up studies have suggested that marine n-3 PUFAs may be associated with a lower risk of ischemic stroke although results have not been consistent and limited knowledge exist on the individual marine n-3 PUFAs and ischemic stroke and its subtypes. The role of ALA is less clear, but most studies have not supported that ALA is appreciably associated with ischemic stroke risk. Some studies have supported that LA might be associated with a lower risk of total ischemic stroke, while limited evidence exist on PUFAs and ischemic stroke subtypes. The associations may depend on the macronutrients that PUFAs replace and this substitution aspect together with focus on dietary patterns represent interesting areas for future research.
BACKGROUNDGenetically 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. OBJECTIVESWe 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. METHODSWe 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. RESULTSFor 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. CONCLUSIONSLipoprotein(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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Limited knowledge exists regarding the association between coronary artery calcium (CAC) deposition in patients with clinical familial hypercholesterolemia (FH) and FH subtypes such as polygenic ...causes. We studied CAC score in patients with clinical FH and subtypes including polygenic causes of FH compared to healthy controls.
In a case-control study, we identified potential clinical FH cases registered with an LDL-C >6.7 mmol/l within a nationwide clinical laboratory database on the Faroe Islands and invited them for diagnostic evaluation according to clinical FH scoring systems. Controls were identified in the background population. All subjects were aged 18–75 years and without a history of cardiovascular disease. FH mutation testing and genotypes of twelve LDL-C associated single nucleotide polymorphisms were determined using conventional methods in selected individuals. CAC scores were assessed by cardiac CT. Odds ratios obtained using multivariate logistic regression were used as measures of association.
A total of 120 clinical FH patients and 117 age- and sex-matched controls were recruited. We found a very low frequency of monogenic FH (3%), but a high level of polygenic FH (60%) in those genetically tested (54%). There was a statistically significant association between the CAC score and a diagnosis of clinical FH with the highest observed odds ratio of 5.59 (95% CI 1.65; 18.94, p = 0.006) in those with a CAC score ≥300 compared to those with a CAC of zero. In supplemental analyses, there was a strong association between CAC scores and clinical FH of a polygenic cause.
We found a statistically significant association between CAC levels and clinical FH with the highest observed risk estimates among clinical FH cases of a presumed polygenic cause.
•High frequency of polygenic hypercholesterolemia in a study population of subjects with clinical familial hypercholesterolemia.•Strong associations between coronary artery calcium levels and clinical familial hypercholesterolemia.•Subjects with polygenic hypercholesterolemia had high levels of coronary artery calcium compared to controls.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The effect of marine omega-3 PUFAs on risk of stroke remains unclear.
We investigated the associations between circulating and tissue omega-3 PUFA levels and incident stroke (total, ischemic, and ...hemorrhagic) in 29 international prospective cohorts. Each site conducted a de novo individual-level analysis using a prespecified analytical protocol with defined exposures, covariates, analytical methods, and outcomes; the harmonized data from the studies were then centrally pooled. Multivariable-adjusted HRs and 95% CIs across omega-3 PUFA quintiles were computed for each stroke outcome.
Among 183 291 study participants, there were 10 561 total strokes, 8220 ischemic strokes, and 1142 hemorrhagic strokes recorded over a median of 14.3 years follow-up. For eicosapentaenoic acid, comparing quintile 5 (Q5, highest) with quintile 1 (Q1, lowest), total stroke incidence was 17% lower (HR, 0.83 CI, 0.76-0.91;
<0.0001), and ischemic stroke was 18% lower (HR, 0.82 CI, 0.74-0.91;
<0.0001). For docosahexaenoic acid, comparing Q5 with Q1, there was a 12% lower incidence of total stroke (HR, 0.88 CI, 0.81-0.96;
=0.0001) and a 14% lower incidence of ischemic stroke (HR, 0.86 CI, 0.78-0.95;
=0.0001). Neither eicosapentaenoic acid nor docosahexaenoic acid was associated with a risk for hemorrhagic stroke. These associations were not modified by either baseline history of AF or prevalent CVD.
Higher omega-3 PUFA levels are associated with lower risks of total and ischemic stroke but have no association with hemorrhagic stroke.
National discharge registers are important and cost-effective data sources for administrative and research purposes, but their value depends much on the validity of the registered data. The objective ...of this study was to assess the validity of heart failure (HF) diagnoses (ICD10: I50.0-I50.9) in the Danish National Patient Register (DNPR).
We reviewed medical records from a random sample of 500 patients with either a primary or a secondary discharge diagnosis of HF registered in the DNPR from any department in Northern Denmark in 2007. We noted symptoms, objective signs, diagnostic imaging and biomarkers and used the European Society of Cardiology definition of HF to categorise patients into definite, probable or non- verified HF.
We classified 305 patients as having definite HF and 113 patients as having probable HF. The remaining cases were classified as non-verified HF. Thus, the positive predictive value (PPV) for definite and probable HF was 83.6% (95% confidence interval (CI): 80.1-86.7%). The PPV increased to 88.0% (95% CI: 84.4-91.0%) when we restricted analyses to primary diagnoses and to 95.2% (95% CI: 89.2-98.4%) when we restricted analyses to HF diagnoses established at cardiology units.
The HF diagnoses (I50.0-I50.9) in the DNPR should be used with caution if validation is not possible. However, restricting analyses to patients registered with a primary diagnosis of HF or patients discharged from cardiology units may be a useful alternative in population-based studies.
none.
not relevant.
The plant-derived omega-3 fatty acid alpha-linolenic acid (ALA) may reduce the risk of cardiovascular disease.
We have investigated associations between the content of ALA in adipose tissue and the ...risk of ischemic stroke and its subtypes.
Incident cases of ischemic stroke among participants enrolled into the Danish Diet, Cancer and Health cohort (n = 57,053) were identified by linkage with the Danish National Patient Register. Subsequently, all potential cases were validated and classified into ischemic stroke subtypes. The fatty acid composition of adipose tissue was determined by gas chromatography in cases and in a randomly drawn sub-cohort (n = 3500). Statistical analyses were performed using weighted Cox regression.
During a median of 13.4 years of follow-up, 1735 cases of total ischemic stroke were identified including 297 cases of large artery atherosclerosis, 772 cases of small-vessel occlusion, 99 cases of cardio-embolism, 91 cases with stroke of other etiology and 476 cases with stroke of undetermined etiology. The median content of ALA in adipose tissue within the sub-cohort was 0.84% (95% central range: 0.53-1.19%). Multivariable analyses showed a U-shaped association between adipose tissue content of ALA and the rate of total ischemic stroke, but this association was not statistically significant (p = 0.172). In analyses of ischemic stroke subtypes, we observed a statistically significant U-shaped association between ALA and the rate of ischemic stroke due to large artery atherosclerosis (p = 0.017), whereas no appreciable association was observed between ALA and the rate of small-vessel occlusion (p = 0.427). A positive but statistically non-significant association was observed between ALA and the rate of ischemic stroke due to cardio-embolism (p = 0.162).
The content of ALA in adipose tissue was statistically non-significantly U-shaped associated with risk of total ischemic stroke. For ischemic stroke subtypes a statistically significant, U-shaped association with large artery atherosclerosis was observed.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
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.
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