Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and ...accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH.
Early diagnosis of HoFH and prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH. We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensive ACVD evaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years, or less if deemed necessary.
This EAS Consensus Panel highlights the need for early identification of HoFH patients, prompt referral to specialized centres, and early initiation of appropriate treatment. These recommendations offer guidance for a wide spectrum of clinicians who are often the first to identify patients with suspected HoFH.
Context: The assignment of direction and causality within networks of observational associations is problematic outside randomized control trials, and the presence of a causal relationship between ...body mass index (BMI) and C-reactive protein (CRP) is disputed. Objective: Using reciprocal Mendelian randomization, we aim to assess the direction of causality in relationships between BMI and CRP and to demonstrate this as a promising analytical technique. Participants and methods: The study was based on a large, cross-sectional European study from Copenhagen, Denmark. Genetic associates of BMI (FTO(rs9939609)) and circulating CRP (CRP(rs3091244)) have been used to reexamine observational associations between them. Results: Observational analyses showed a strong, positive association between circulating CRP and BMI (change in BMI for a doubling in logCRP of 1.03 kg m−2 (95% confidence interval (95% CI): 1.00, 1.07), P<0.0001). Analysis using CRP(rs3091244) to re-estimate the causal effect of circulating CRP on BMI yielded null effects (change in BMI for a doubling in logCRP of −0.24 kg m−2 (95% CI: −0.58, 0.11), P=0.2). In contrast, analysis using FTO(rs9939609) to assess the causal effect of BMI on circulating CRP confirmed observational associations (ratio of geometric means of CRP per s.d. increase in BMI 1.41 (95% CI: 1.10, 1.80), P=0.006). Conclusions: Taken together, these data suggest that the observed association between circulating CRP and measured BMI is likely to be driven by BMI, with CRP being a marker of elevated adiposity. More generally, the method of reciprocal randomization has general applicability in determining the direction of causation within inter-correlated networks of metabolic components.
Background and objectives
Coffee intake is associated with low risk of symptomatic gallstone disease (GSD). We tested the hypothesis that high coffee intake causally protects against symptomatic GSD ...using a Mendelian randomization design.
Methods
First, we tested whether high coffee intake was associated with low risk of GSD in 104 493 individuals from the general population. Mean follow‐up was 8 years (range: <1–13 years). Secondly, we tested whether two genetic variants near CYP1A1/A2 (rs2472297) and AHR (rs4410790), combined as an allele score, were associated with higher coffee intake measured as a continuous variable. Thirdly, we tested whether the allele score was associated with lower risk of GSD in 114 220 individuals including 7294 gallstone events. Mean follow‐up was 38 years (range: <1–40 years).
Results
In observational analysis, those with coffee intake of >6 cups daily had 23% lower risk of GSD compared to individuals without coffee intake hazard ratio (HR) = 0.77 (95% confidence interval: 0.61–0.94). In genetic analysis, there was a stepwise higher coffee intake of up to 41% (caffeine per day) in individuals with 4 (highest) versus 0 (lowest) coffee intake alleles (P for trend = 3 x 10−178) and a corresponding stepwise lower risk of GSD up to 19%HR = 0.81 (0.69–0.96). The estimated observational odds ratio for GSD for a one cup per day higher coffee intake was 0.97 (0.96–0.98), equal to 3% lower risk. The corresponding genetic odds ratio was 0.89 (0.83–0.95), equal to 11% lower risk.
Conclusion
High coffee intake is associated observationally with low risk of GSD, and with genetic evidence to support a causal relationship.
Background
Elevated plasma levels of bilirubin, an endogenous antioxidant, have been associated with reduced risk of ischaemic heart disease (IHD) and myocardial infarction (MI). Whether this is a ...causal relationship remains unclear.
Objective
We tested the hypothesis that elevated plasma bilirubin is causally related to decreased risk of IHD and MI.
Design
We used a Mendelian randomization approach and three independent studies from Copenhagen, Denmark. We measured bilirubin in 43 708 white individuals from the general population, and genotyped rs6742078 G>T in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene in 67 068 individuals, of whom 11 686 had IHD.
Results
Third versus first tertile of baseline bilirubin levels was associated with 134% increased bilirubin levels, with sex‐ and age‐adjusted hazard ratios (HRs) of 0.86 95% confidence interval (CI), 0.76–0.98; P = 0.02 for IHD and 0.81 (95% CI, 0.66–0.99; P = 0.04) for MI, but with corresponding multifactorially adjusted HRs of 0.93 (95% CI, 0.82–1.06; P = 0.29) and 0.90 (95% CI, 0.73–1.12; P = 0.35). UGT1A1 rs6742078 TT versus GG genotype was associated with 95% increased bilirubin levels (P < 0.001); TT versus GG genotype was associated with odds ratios (ORs) of 1.03 (95% CI, 0.96–1.11; P = 0.73) for IHD and 1.01 (95% CI, 0.92–1.12; P = 0.68) for MI. Finally, in a meta‐analysis of the present three studies and eight previous studies including a total of 14 711 cases and 60 324 controls, the random effects OR for ischaemic cardiovascular disease for genotypes with approximately 100% increased bilirubin levels versus reference genotypes was 1.01 (95% CI, 0.88–1.16).
Conclusion
These data suggest that plasma bilirubin is not causally associated with risk of IHD.
Christensen AH, Andersen CB, Tybjærg‐Hansen A, Haunso S, Svendsen JH. Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy.
A ...single report has associated mutations in TMEM43 (LUMA) with a distinctive form of arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed at performing mutational analysis of the gene and characterizing the associated immunohistochemical features. Sixty‐five unrelated patients (55 fulfilling Task Force criteria and 10 borderline cases) were screened for mutations in TMEM43. Immunohistochemistry with anti‐TMEM43, anti‐plakoglobin, anti‐plakophilin‐2, anti‐connexin‐43, and anti‐emerin antibodies was performed on myocardium from TMEM43‐positive patients (n = 3) and healthy controls (n = 3). The genetic screening identified heterozygous variants in two families: one reported mutation (c.1073C> T; in two related patients) and one novel variant (c.705+ 7G> A; in one patient) of unknown significance. All three patients fulfilled Task Force criteria and did not carry mutations in any other ARVC‐related gene. Immunostaining with TMEM43 antibody showed intense staining of the sarcolemma. The signal level was reduced in all the three TMEM43‐positive patients. Immunostaining with plakoglobin‐specific antibody also showed reduced signal levels in the three carriers. All patients displayed a similar immunoreactive signal for plakophilin‐2, connexin‐43, and emerin. In conclusion, two TMEM43 sequence variants were identified in this Danish ARVC cohort. Evaluation of the expression of TMEM43 showed a unique cardiac localization. The immunoreactive signal for the desmosomal protein plakoglobin was reduced in mutation carriers. The TMEM43 gene underlies a distinctive form of ARVC which may share a final common pathway with desmosome‐associated ARVC.
. Langsted A, Freiberg JJ, Tybjærg‐Hansen A, Schnohr P, Jensen GB, Nordestgaard BG (Herlev Hospital, Herlev; University of Copenhagen; Bispebjerg Hospital; and Rigshospitalet, Copenhagen Ø, ...Denmark). Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow‐up. J Intern Med 2011; 270: 65–75.
Objectives. We compared the ability of very high levels of nonfasting cholesterol and triglycerides to predict risk of myocardial infarction and total mortality.
Design. Prospective study from 1976 to 1978 until 2007.
Setting. Danish general population.
Participants. Randomly selected population of 7581 women and 6391 men, of whom 768 and 1151 developed myocardial infarction and 4398 and 4416 died, respectively. Participation rate was 72%, and follow‐up was 100% complete. Less than 2% of participants were taking lipid‐lowering therapy.
Results. Compared to women with cholesterol <5 mmol L−1, multivariate‐adjusted hazard ratios for myocardial infarction ranged from 1.3 95% confidence interval (CI): 0.9–1.8 for a cholesterol level of 5.0–5.99 mmol L−1 to 2.5 (95%CI: 1.6–4.0) for cholesterol ≥9 mmol L−1 (trend: P < 0.0001). Compared with women with nonfasting triglycerides <1 mmol L−1, hazard ratios for myocardial infarction ranged from 1.5 (95%CI: 1.2–1.8) for triglycerides of 1.0–1.99 mmol L−1 to 4.2 (95%CI: 2.5–7.2) for triglycerides ≥5 mmol L−1 (p<0.0001). In men, corresponding hazard ratios ranged from 1.2 (95%CI: 1.0–1.5) to 5.3 (95%CI: 3.6–8.0) for cholesterol (P < 0.0001) and from 1.3 (95%CI: 1.0–1.6) to 2.1 (95%CI: 1.5–2.8) for triglycerides (P < 0.0001). Increasing cholesterol levels were not consistently associated with total mortality in women (trend: P = 0.39) or men (P = 0.02). By contrast, compared with women with triglycerides <1 mmol L−1, multivariate‐adjusted hazard ratios for total mortality ranged from 1.1 (95%CI: 1.0–1.2) for triglycerides of 1.0–1.99 mmol L−1 to 2.0 (95%CI: 1.5–2.9) for triglycerides ≥5 mmol L−1 (trend: P < 0.0001); corresponding hazard ratios in men ranged from 1.1 (95%CI: 1.0–1.2) to 1.5 (95%CI: 1.2–1.7) (P < 0.0001).
Conclusions. Stepwise increasing levels of nonfasting cholesterol and nonfasting triglycerides were similarly associated with stepwise increasing risk of myocardial infarction, with nonfasting triglycerides being the best predictor in women and nonfasting cholesterol the best predictor in men. Even more surprisingly, only increasing levels of nonfasting triglycerides were associated with total mortality, whereas increasing cholesterol levels were not.
Summary
Background
Use of oral contraceptives with estrogen and hormone replacement therapy with estrogen or testosterone are associated with increased risk of venous thromboembolism (VTE). However, ...whether endogenous estradiol and testosterone concentrations are also associated with risk of VTE is unknown.
Objective
We tested the hypothesis that elevated endogenous total estradiol and total testosterone concentrations are associated with increased risk of VTE in the general population.
Methods
We studied 4658 women, not receiving exogenous estrogen, and 4673 men from the 1981–1983 Copenhagen City Heart Study, who had estradiol and testosterone concentrations measured. Of these, 636 developed VTE (deep venous thrombosis DVT and/or pulmonary embolism PE) during a follow‐up of 21 years (range, 0.02–32 years). Associations between endogenous estradiol and testosterone concentrations and risk of VTE were estimated by Cox proportional hazards regression with time‐dependent covariates and corrected for regression dilution bias.
Results
Multifactorially adjusted hazard ratios of VTE for individuals with estradiol levels >75th vs. ≤25th percentile were 0.84 (95%CI, 0.25–2.85), 1.05 (0.53–2.08) and 1.05 (0.03–35.13) for pre‐ and post‐menopausal women and men, respectively. For testosterone, corresponding risk estimates were 0.64 (0.03–12.32), 1.11 (0.66–1.86) and 1.30 (0.62–2.73). In addition, no associations were observed between extreme hormone percentiles (>95th vs. ≤75th) and risk of DVT, PE or recurrent VTE.
Conclusion
This prospective study suggests that high endogenous concentrations of estradiol and testosterone in women and men in the general population are not associated with increased risk of VTE, DVT or PE.
Summary
Background
Vitamin D has potential antithrombotic effects, suggesting that vitamin D analogs could be used as adjunctive antithrombotic agents. However, epidemiologic evidence of an ...association between reduced 25‐hydroxyvitamin D concentrations and the risk of venous thromboembolism is lacking.
Objectives
To test the hypothesis that reduced plasma 25‐hydroxyvitamin D concentrations are associated with an increased risk of venous thromboembolism in the general population.
Methods
We prospectively studied 18 791 participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. During up to 30 years of follow‐up, 950 participants were diagnosed with venous thromboembolism. Plasma 25‐hydroxyvitamin D concentrations were adjusted for seasonal variation.
Results
The cumulative incidence of venous thromboembolism as a function of age increased with decreasing tertiles of seasonally adjusted plasma 25‐hydroxyvitamin D (log‐rank trend: P = 4 × 10−4). On comparison of participants in the lowest and the highest tertile of plasma 25‐hydroxyvitamin D concentrations, the crude risk estimate in a model adjusted for age and sex was a 37% (95% confidence interval CI 15–64%) increased risk of venous thromboembolism. The corresponding risk increase in a model adjusted for age, sex, body mass index, smoking and cancer was 26% (95% CI 5–51%), and in a multivariable‐adjusted model also including physical activity, hormone replacement therapy, menopausal status, oral contraception use and lipid‐lowering therapy it was 28% (95% CI 6–53%). Furthermore, corresponding risk increases with attempts to correct for regression dilution bias were 103% (95% CI 37–202%), 70% (95% CI 14–155%) and 73% (95% CI 15–160%) in the three models, respectively.
Conclusion
In these large general population studies, we observed a stepwise increasing risk of venous thromboembolism with decreasing tertiles of seasonally adjusted plasma 25‐hydroxyvitamin D concentrations.
To explore the causal effect of long-term alcohol consumption on coronary heart disease risk factors.
We used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal ...effect of long-term alcohol consumption on body mass index (BMI), blood pressure (BP), lipids, fibrinogen, and glucose. Analyses were undertaken in 54 604 Danes (mean age 56 years). Both confounder-adjusted multivariable and IV analyses suggested that a greater alcohol consumption among those who drank any alcohol resulted in a higher BP mean difference in SBP per doubling of alcohol consumption among drinkers: 0.76 mmHg (95% CI: 0.63, 0.90) from multivariable analyses and 0.94 mmHg (-3.03, 4.69) from IV analyses; P-value for difference in these results = 0.95. The positive association of alcohol with HDLc in the multivariable analyses 4.9% (4.7, 5.1) appeared stronger than in the IV analyses 1.5% (-4.5, 7.4), and the weak inverse association with fibrinogen in the multivariable analysis -2.0% (-2.1, -1.8) was not present in the IV analyses 0.6% (-3.8, 5.0), but statistically the results for both of these could not be reliably distinguished from each other (P-values 0.21 and 0.32, respectively). The weak inverse association of alcohol with BMI -0.13 kg/m(2) (-0.16, -0.10) and with triglycerides -0.4% (-0.7, 0.4) in multivariable analyses were in contrast to the strong positive association of alcohol with BMI 1.37 kg/m(2) (0.59, 2.15) and the strong inverse association with triglycerides -14.9% (-25.6, -4.3) in IV analyses; P = 0.006 and 0.01, respectively, for difference between the two. Alcohol was not associated with non-HDLc or glucose.
Our results show adverse effects of long-term alcohol consumption on BP and BMI. We also found novel evidence for a potentially beneficial effect on triglyceride levels, which needs further replication.
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